Venglustat in combination with strong or moderate inhibitors of CYP3A4

Abstract

Provided herein are methods in which a patient is administered benglustat in combination with an inhibitor of cytochrome CYP3A4, which may involve making specific adjustments to the benglustat dosage to optimize the patient's clinical response.

Description

[Technical Field]

[0001] Provided herein are methods in which a patient is administered benglustat in combination with an inhibitor of cytochrome CYP3A4, such as itraconazole or fluconazole, which may involve making specific adjustments to the benglustat dosage to optimize the patient's clinical response. [Background technology]

[0002] Venglustat (also known as (S)-quinuclidin-3-yl 2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-ylcarbamate) is a small molecule drug proposed to be useful in the treatment of conditions including 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 incorporated herein by reference in their entirety. It has been suggested that benglustat, an inhibitor of the enzyme glucosylceramide synthase (GCS), may act in these treatments by lowering glycolipid levels (e.g., in lysosomal storage diseases), reducing protein aggregation (e.g., in proteinopathies), decreasing apoptosis (e.g., in cystic diseases) or improving ciliary function in ciliated epithelial cells (e.g., in ciliopathies).

[0003] Small molecule GCS inhibitors, such as benglustat, are primarily intended for regular (e.g., daily) oral administration. Orally administered compounds may undergo first-pass metabolic inactivation by the liver, which can reduce oral bioavailability. Therefore, oral dosage forms may require a larger dose to achieve therapeutic efficacy than would be required if the active agent were administered via another route (e.g., intravenously). Furthermore, significant interactions may exist between orally administered drugs and agents that act to regulate the drug's metabolic pathway (drug-drug interactions; DDIs).

[0004] In the case of benglustat, the liver enzyme cytochrome P 450 Although CYP3A4 (CYP3A4) is involved in the metabolic pathway, the clinical significance of CYP3A4 involvement has not been established (see, e.g., Peterschmitt et al., Clin. Pharmacol. Drug Dev. (2021) 10(1):86-98). Nevertheless, some clinical studies of benglustat have excluded participants receiving concomitant treatment with moderate or strong CYP3A4 inhibitors (see, e.g., Peterschmitt et al., J. Parkinson's Dis. (2022) 12:557-570 and its supporting information). Summary of the Invention [Problem to be solved by the invention]

[0005] Patients requiring treatment for the above conditions may suffer from comorbid disorders that require additional pharmacological intervention. Many of these patients may particularly need to co-administer one or more pharmacological agents that are CYP3A4 inhibitors, and as a result, the combination of pharmacological agents may be contraindicated due to DDI. Therefore, there is a need to develop safe and effective dosing regimens, dosage forms, and treatment methods using benglustat to account for the metabolic effects associated with CYP3A4. [Means for solving the problem]

[0006] This disclosure describes clinical trials conducted to evaluate the effect of strong CYP3A4 inhibitors on benglustat exposure in vivo. This disclosure also describes in silico studies evaluating the effect of various other CYP3A4 inhibitors on benglustat exposure. These results have enabled the development of benglustat dosing regimens, dosage forms, and treatment methods tailored to specific CYP3A4 inhibitors when co-administered with those drugs.

[0007] Accordingly, in a first aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering an effective amount of benglustat or a pharmaceutically acceptable salt thereof to the subject, wherein the subject is concomitantly receiving a strong or moderate inhibitor of CYP3A4.

[0008] A further aspect provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of benglustat or a pharmaceutically acceptable salt thereof, wherein the subject is concurrently administered a CYP3A4 inhibitor, whereby the plasma exposure (e.g., AUC) of benglustat is increased by about 5% to 25% compared to the exposure resulting from administration of benglustat at the same dosage, form, and regimen in the absence of the CYP3A4 inhibitor. In embodiments, benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 12 mg / day or about 15 mg / day (calculated as the free base).

[0009] In embodiments, the CYP3A4 inhibitor is a potent inhibitor that increases the plasma exposure of benglustat by about 60% to 120% compared to the exposure resulting from administration of benglustat at the same dose, form, and regimen in the absence of the CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dose of about 4 mg to 15 mg / day (calculated as the free base). In embodiments, benglustat or a pharmaceutically acceptable salt thereof is administered at a dose of about 8 mg / day (calculated as the free base).

[0010] In another embodiment, the CYP3A4 inhibitor is a moderate inhibitor that increases the plasma exposure of benglustat by about 40% to 60% compared to the exposure resulting from administration of benglustat at the same dose, form, and regimen in the absence of the CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dose of about 12 mg to 15 mg per day (calculated as the free base). In an embodiment, benglustat or a pharmaceutically acceptable salt thereof is administered at a dose of about 15 mg per day (calculated as the free base).

[0011] In embodiments, benglustat is in the form of benglustat free base, a pharmaceutically acceptable salt of benglustat or a prodrug of benglustat, optionally benglustat L-malate.

[0012] In embodiments, benglustat or a pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered in combination, e.g., in the same pharmaceutical composition.

[0013] In embodiments, benglustat or a pharmaceutically acceptable salt thereof is administered orally and the CYP3A4 inhibitor is administered transmucosally, intravenously, or orally.

[0014] In embodiments, 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).

[0015] In embodiments, the subject has a comorbidity selected from a fungal infection, a viral infection, a bacterial infection, a mood disorder, and cancer.

[0016] The present disclosure also provides benglustat or a pharmaceutically acceptable salt thereof (or a combination of benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor, such as a composition comprising benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor) for use in the methods defined above.

[0017] The present disclosure also provides the use of benglustat or a pharmaceutically acceptable salt thereof (or a combination of benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor, such as a composition comprising benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor) in the manufacture of a medicament for use in a method as defined above.

[0018] The present disclosure also provides a method for optimizing (e.g., reducing) the dosage of benglustat in a subject being treated or intended to be treated with benglustat or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject a strong or moderate CYP3A4 inhibitor.

[0019] The present disclosure also provides a method for minimizing a drug-drug interaction between benglustat and a moderate or strong CYP3A4 inhibitor in a subject suffering from a disease or disorder amenable to treatment with benglustat or a pharmaceutically acceptable salt thereof, the method comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with said CYP3A4 inhibitor compared to the exposure that would result from administration of benglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) adjusting the dosage of benglustat or a pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

[0020] The present disclosure also provides a method for establishing the correct dosage of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, the method comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor compared to the exposure resulting from administration of benglustat in the same dosage, form and regimen in the absence of said CYP3A4 inhibitor; and (ii) reducing the dosage of benglustat or a pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

[0021] The present disclosure also provides a method for improving the dosing regimen of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor compared to the exposure resulting from administration of benglustat in the same dosage, form, and regimen in the absence of the CYP3A4 inhibitor; and (ii) reducing the dosage of benglustat or a pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

[0022] The present disclosure also provides a method for managing the risk of benglustat / CYP3A4 inhibitor interaction in a subject having a disease or disorder amenable to treatment with benglustat or a pharmaceutically acceptable salt thereof, the method comprising: (i) initiating treatment in the subject with benglustat or a pharmaceutically acceptable salt thereof at a standard prescribed dose; (ii) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor compared to the exposure that would result from administration of benglustat 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%.

[0023] The present disclosure also provides the use of a strong or moderate CYP3A4 inhibitor in a method for (a) establishing the correct dosage of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, (b) improving the dosing regimen of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, or (c) managing the risk of benglustat / CYP3A4 inhibitor interaction in a subject having a disease or disorder amenable to treatment with benglustat or a pharmaceutically acceptable salt thereof, wherein the subject is receiving or is intended to be receiving said CYP3A4 inhibitor.

[0024] The present disclosure also provides a method for inhibiting CYP3A4 activity in a subject being treated with benglustat or a pharmaceutically acceptable salt thereof, the method comprising administering benglustat or a pharmaceutically acceptable salt thereof concomitantly with a strong or moderate CYP3A4 inhibitor.

[0025] The present disclosure also provides a method for improving the therapeutic response to benglustat treatment in a subject in need thereof, comprising administering benglustat or a pharmaceutically acceptable salt thereof concomitantly with a strong or moderate CYP3A4 inhibitor.

[0026] The present disclosure also provides pharmaceutical compositions (e.g., oral pharmaceutical dosage forms) comprising benglustat or a pharmaceutically acceptable salt thereof in combination with a strong or moderate CYP3A4 inhibitor and at least one pharmaceutically acceptable excipient.

[0027] In embodiments, the composition is formulated for oral administration, hi embodiments, the composition is in 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).

[0028] The present disclosure also provides a composition as defined above for use in a method as defined above.

[0029] Additional features and advantages of the compositions and methods disclosed herein will become apparent from the following detailed description. [Brief explanation of the drawings]

[0030] [Figure 1] 1 shows the study design of the clinical trial described in Example 4. [Figure 2] Mean (+SD) plasma concentrations of benglustat are shown after a single dose of 15 mg benglustat alone (calculated as the free base - open triangles) and after co-administration of 15 mg benglustat with multiple doses of itraconazole (100 mg BID - open circles). [Figure 3] Figure 3 shows (Cartesian scale) the observed (clinical trial) and mean (5th and 95th percentile) predicted benglustat plasma concentrations in healthy male subjects after single oral doses of 11.2 mg (Figure 3A), 18.6 mg (Figure 3B), and 112 mg (Figure 3C) of benglustat. Gray lines represent predictions from individual trials. Dashed lines represent the 5th and 95th percentiles of the entire hypothetical population. Solid black lines represent simulated mean plasma concentration-time profiles. Open circles represent individual concentrations observed in the clinical trial. [Figure 4] Figure 4 shows (semi-logarithmic scale) the observed (clinical trial) and mean (5th and 95th percentile) predicted benglustat plasma concentrations in healthy male subjects after single oral doses of 11.2 mg (Figure 4A), 18.6 mg (Figure 4B), and 112 mg (Figure 4C) of benglustat. Gray lines represent predictions from individual trials. Dashed lines represent the 5th and 95th percentiles of the entire hypothetical population. Solid black lines represent simulated mean plasma concentration-time profiles. Open circles represent individual concentrations observed in the clinical trial. [Figure 5]Figure 5 shows (Cartesian scale) the observed (clinical trial) and mean (5th and 95th percentile) predicted benglustat plasma concentrations in healthy male subjects after repeated QD oral administration of 3.72 mg (Figure 5A), 7.44 mg (Figure 5B), and 14.9 mg (Figure 5C) of benglustat. Gray lines represent predictions from individual trials. Dashed lines represent the 5th and 95th percentiles of the entire hypothetical population. Solid black lines represent simulated mean plasma concentration-time profiles. Open circles represent individual concentrations observed in the clinical trial. [Figure 6] Figure 6 shows (semi-logarithmic scale) the observed (clinical trial) and mean (5th and 95th percentile) predicted benglustat plasma concentrations in healthy male subjects after repeated QD oral administration of 3.72 mg (Figure 6A), 7.44 mg (Figure 6B), and 14.9 mg (Figure 6C) of benglustat. Gray lines represent predictions from individual trials. Dashed lines represent the 5th and 95th percentiles of the entire hypothetical population. Solid black lines represent simulated mean plasma concentration-time profiles. Open circles represent individual concentrations observed in the clinical trial. [Figure 7] Figure 7 shows simulated mean (5th and 95th percentile) benglustat plasma concentrations in healthy male subjects after a single oral dose of 15 mg benglustat with (FIG. 7A) and (FIG. 7B) co-administration of 100 mg itraconazole BID (Cartesian scale). Individual observed benglustat concentrations (open circles) are overlaid on the simulated profiles. In each case, the solid black line represents the simulated mean plasma concentration-time profile of benglustat without itraconazole interaction, and the solid gray lines represent the 5th and 95th percentiles of the entire hypothetical population. The dashed black line represents the simulated mean plasma concentration-time profile of benglustat with itraconazole interaction, and the dashed gray lines represent the 5th and 95th percentiles of the entire hypothetical population. The open circles represent the individual concentrations observed in the study of Example 4. [Figure 8]Figure 8 shows simulated mean (5th and 95th percentile) benglustat plasma concentrations in healthy male subjects after a single oral dose of 15 mg benglustat with (FIG. 8A) and (FIG. 8B) co-administration of 100 mg itraconazole BID (semi-log scale). Individual observed benglustat concentrations (open circles) are overlaid on the simulated profiles. In each case, the solid black line represents the simulated mean plasma concentration-time profile of benglustat without itraconazole interaction, and the solid gray lines represent the 5th and 95th percentiles of the entire hypothetical population. The dashed black line represents the simulated mean plasma concentration-time profile of benglustat with itraconazole interaction, and the dashed gray lines represent the 5th and 95th percentiles of the entire hypothetical population. The open circles represent the individual concentrations observed in the study of Example 4. [Figure 9] Figure 9A shows the observed (Example 4) and mean (5th and 95th percentile) predicted plasma concentrations of itraconazole (Figure 9A) and its primary metabolite hydroxyitraconazole (Figure 9B) in healthy male subjects after 100 mg itraconazole BID (Cartesian scale). The solid gray line represents predictions from individual trials. The dashed lines represent the 5th and 95th percentiles of the entire hypothetical population. The solid black line represents the simulated mean plasma concentration-time profile. The gray dots (approximately 125, 160, and 220 hours) represent the individual concentrations observed in the study of Example 4. [Figure 10] FIG. 10A shows the observed (Example 4) and mean (5th and 95th percentile) predicted plasma concentrations of itraconazole (FIG. 10B) and its primary metabolite hydroxyitraconazole in healthy male subjects after 100 mg itraconazole BID (semi-log scale). The solid gray lines represent predictions from individual trials. The dashed lines represent the 5th and 95th percentiles of the entire hypothetical population. The solid black lines represent the simulated mean plasma concentration-time profiles. The gray dots (approximately 125, 160, and 220 hours) represent the individual concentrations observed in the study of Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0031] Specific embodiments of the present disclosure will now be described with reference to preparations and schemes, but it should be understood that such embodiments are illustrative only and merely a few of the many possible specific embodiments that may represent applications of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art upon consideration of the benefit of this disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0032] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of this disclosure, exemplary methods, devices, and materials are described herein. All technical and patent publications mentioned herein are incorporated by reference in their entirety.

[0033] The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art. See, e.g., Michael R. Green and Joseph Sambrook, Molecular Cloning (4 thed.,Cold Spring Harbor Laboratory Press 2012);the series Ausubel et al.eds.(2007)Current Protocols in Molecular Biology;the series Methods in Enzymology(Academic Press,Inc.,N.Y.);MacPherson et al.(1991)PCR 1:A Practical Approach(IRL Press at Oxford University Press);MacPherson et al.(1995)PCR 2:A Practical approach;Harlow and Lane eds.(1999)Antibodies,A Laboratory Manual;Freshney(2005)Culture of Animal Cells:A Manual of Basic Technique,5 thedition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Patent No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Herzenberg et al. eds (1996) Weir’s Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3 rd edition (Cold Spring Harbor Laboratory Press (2002)); See Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press).

[0034] All numerical designations (e.g., pH, temperature, time, concentration, molecular weight, etc., including ranges) are approximations that are varied (+) or (-) by increments of, for example, 0.1 or 1.0, where appropriate. It is understood, although not always explicitly stated, that all numerical designations are preceded by the term "about," which is used to indicate the conventional level of variability. For example, a numerical designation that is "about" a given value may vary by ±10% of said value; alternatively, the variation may be ±5%, ±2%, or ±1% of this value. It is also understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents thereof are known in the art.

[0035] As used in this specification and claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "inhibitor" includes a plurality of inhibitors, including mixtures thereof. Unless otherwise specified or clear from the context, the term "or" as used herein is understood to be inclusive. The term "comprising" is used herein to mean, and is used interchangeably with, the phrase "including but not limited to."

[0036] As used herein, the terms "comprising" or "comprises" are intended to mean that the compositions and methods include the recited elements, but do not exclude other elements. "Consisting essentially of," when used to define compositions and methods, is intended to mean excluding other elements that are essential for the purpose described. Thus, a composition consisting essentially of the elements defined herein would not exclude trace contaminants from isolation and purification methods and pharmaceutically acceptable carriers, e.g., phosphate-buffered saline, preservatives, and the like. "Consisting of" is intended to mean the exclusion of other ingredients, beyond trace elements, as well as substantial method steps for administering a composition of the present disclosure or process steps for producing the composition or achieving an intended result. Embodiments defined by each of these transition terms are within the scope of the present disclosure. The use of the term "comprising" herein is intended to encompass both "consisting essentially of" and "consisting of."

[0037] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to a human.

[0038] As used herein, the term "healthy individual" typically refers to an individual who is not suffering from a condition suitable for treatment with benglustat. For example, a healthy individual may be an individual who is not suffering 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 a GBA mutation. Indeed, a healthy individual may lack a mutation in any gene encoding an enzyme involved in the glycosphingolipid pathway, such as a mutation in a gene encoding ceramide synthase, glucosylceramide synthase, galactosylceramide synthase, lactosylceramide synthase, sphingomyelin synthase, ceramidase, glucocerebrosidase, saposin, galactosylceramide β-galactosidase, acid sphingomyelinase, arylsulfatase A, α-galactosidase A, β-hexosaminidase (e.g., Hex A or Hex B), sialidase, GM1-β-galactosidase, GM2 ganglioside activator protein, glucosyltransferase, and galactosyltransferase.

[0039] "Administering" is defined herein as a means of providing a drug (e.g., an active ingredient) or a composition containing a drug to a subject in such a manner that the drug is internalized in the subject's body. Such administration can be by any route, including, but not limited to, oral, dermal, transdermal, transmucosal (e.g., vaginal, rectal, buccal, or sublingual), injection (e.g., subcutaneous, intravenous, intraperitoneal, intrathecal, intramuscular, intradermal), and inhalation (e.g., pulmonary, intranasal). Pharmaceutical formulations are, of course, administered in a form appropriate for each administration route. Administration can also be local or systemic in nature. For example, oral and injectable administration routes generally provide systemic exposure, while some administration routes provide only local exposure, such as topical dermal administration and intradermal injection. Intranasal inhalation can provide either local or systemic exposure. The compositions and methods of the present disclosure are typically intended for enteral, e.g., oral, administration.

[0040] As used herein, "concurrently" and "simultaneously," when referring to therapeutic use, refer to the administration of two or more active ingredients to a patient as part of a regimen for treating a disease or disorder, regardless of whether the two or more active agents are administered at the same or different times or by the same or different routes of administration. As used herein, the terms "concomitant with" and "in conjunction with" are intended to have equivalent meanings. The simultaneous administration of two or more active ingredients can be at different times on the same day or on different days or at different frequencies. The simultaneous administration of two or more active agents may be intended to treat a single disease or disorder in a patient, but is typically used herein to refer to the administration of two or more active agents that are effective to treat two or more different diseases or disorders, e.g., each active agent is effective to treat a distinct disease or disorder independently of the other active agents.

[0041] As used herein, the term "concurrently" when referring to therapeutic use refers to simultaneous or near-simultaneous administration of two or more active ingredients, typically by the same route of administration. This can refer to administration of two or more active ingredients in a single dosage form, or in multiple separate dosage forms administered simultaneously or near-simultaneously. For example, this can refer to administering a single oral tablet or capsule containing two or more active ingredients to a patient, or to administering two or more oral tablets or capsules containing two or more active ingredients between them. The two or more active agents are typically intended to treat two or more different diseases or disorders, e.g., each active agent is effective in treating a distinct disease or disorder independently of the other active agents.

[0042] As used herein, the term "separately," when referring to therapeutic use, refers to simultaneous or near-simultaneous administration of two or more active ingredients by different routes of administration, or administration of two or more active ingredients at different times by the same or different routes of administration. For example, the term "separately" includes administering one active ingredient by injection or inhalation while administering a separate active ingredient orally, provided that both administrations occur at approximately the same time. Furthermore, the term "separately" includes administering one active ingredient orally at a particular time, e.g., in the morning, and administering a separate active ingredient orally at a different time, e.g., one or three hours later, or in the afternoon or evening, or on a different day. Thus, separate administration also encompasses, for example, a dosing regimen in which one drug is taken on day 1, day 3, day 5, etc., and another drug is taken on day 2, day 4, day 6, etc. Again, the two or more active ingredients or drugs are typically 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 agents.

[0043] The phrase "simultaneously or nearly simultaneously" is generally understood to mean two events occurring less than 30 minutes apart, e.g., less than 20 minutes, or less than 15 minutes, or less than 10 minutes, or less than 5 minutes. Where the events themselves occur over a period of time, e.g., intravenous administration of a drug over a 60-minute period, "simultaneously or nearly simultaneously" includes any overlap between such periods or the beginning of such period within about 30 minutes of the end of the previous period.

[0044] "Treating" or "treatment" of a disease includes: (1) inhibiting the disease, i.e., halting or reducing the onset of the disease or its clinical symptoms, and / or (2) palliating the disease, i.e., causing regression of the disease or its clinical symptoms. "Preventing" or "prevention" of a disease includes preventing clinical symptoms of the disease from developing in patients who may be predisposed to the disease but who have not yet experienced or displayed symptoms of the disease. A disease that is "susceptible to" or "treatable" with a particular active agent is one that can be treated and / or prevented by the active agent in at least some patients who are afflicted with or susceptible to the disease.

[0045] The term "suffering," in conjunction with the term "treatment," refers to a patient or individual who has been diagnosed with a disease. The term "suffering," in conjunction with the term "prevention," refers to a patient or individual who is susceptible to a disease. A patient may also be said to be "at risk for" a disease because of a history of the disease in their family or the presence of a genetic mutation associated with the disease. A patient at risk for a disease has not yet developed all or some of the characteristic symptoms of the disease.

[0046] An "effective amount" or "therapeutically effective amount" is an amount sufficient to produce a beneficial or desired result. An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery depends on many variables, including the duration for which individual dosage units are used, the bioavailability of the therapeutic agent, and the route of administration. However, it is understood that the specific dosage level of a therapeutic agent of the present disclosure for any particular subject will depend on a variety of factors, including, for example, the activity of the specific compound used, the subject's age, weight, general health, sex, and diet, the time of administration, the severity of the particular disorder being treated, and the mode of administration. Typically, dose-effect relationships from in vitro and / or in vivo studies can provide useful guidance regarding appropriate dosages for initial patient administration. In general, one will desire to administer an amount of compound effective to achieve serum levels commensurate with concentrations found to be effective in vitro. Determination of these parameters is well within the skill of one of ordinary skill in the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and are described in standard texts. Consistent with this definition, as used herein, the term "therapeutically effective amount" is an amount sufficient to treat (e.g., ameliorate) one or more symptoms associated with a disease or disorder described herein, ex vivo, in vitro, or in vivo. A "standard prescribed dose" refers to the recommended amount of a therapeutic agent for a subject in the absence of variables that may require dose adjustment, e.g., co-administration with one or more additional agents as defined herein. When such variables exist, an "adjusted dose" or "adjusted effective amount" may be administered—which may be the same or a different amount of therapeutic agent compared to a "standard prescribed dose" or "effective amount" for a different (e.g., average) subject.

[0047] As used herein, "CYP" is an abbreviation for Cytochrome P450 (or Cytochrome Oxidase P450), a family of mammalian enzymes that are primarily expressed in the liver and are primarily responsible for the oxidative metabolism of many drugs. There are at least 57 common types of CYP enzymes, which are classified into families. The CYP3A family includes, among other enzymes, the related CYP3A4 and CYP3A5 enzymes, which collectively account for the majority of mammalian drug metabolism. CYP3A4 is the primary cytochrome involved in the metabolism of benglustat, responsible for approximately 80% of benglustat metabolism in human liver microsomes.

[0048] As used herein, the term "inhibitor" has its commonly recognized pharmacological meaning. Thus, an inhibitor is a compound (typically a small molecule) that competitively or noncompetitively (e.g., allosterically) inhibits the function of an enzyme, receptor, or other macromolecular target (e.g., a protein). Inhibitors generally act by either binding to the active site of an enzyme or receptor, blocking access by normal substrates, or binding to an allosteric site that causes a conformational change in the enzyme or receptor that reduces the activity of the enzyme or receptor. Competitive inhibitors bind to the active site and can cause reversible or irreversible inhibition, the latter often due to covalent binding to the active site. Inhibition of an enzyme in the presence of a compound can also occur indirectly, for example, when one or more metabolites of the compound are themselves inhibitors of the enzyme (e.g., reversible or irreversible and / or competitive or noncompetitive inhibitors).

[0049] Therefore, as used herein, the term "CYP3A4 inhibitor" refers to a small molecule compound that competitively or non-competitively inhibits the enzymatic activity of the CYP3A4 enzyme, reversibly or irreversibly. CYP3A4 inhibitors can be described as strong, moderate, or weak (see, for example, "Common Medications Classified as Weak, Moderate, and Strong Inhibitors of CYP3A4," EBM Consult (October 2015) (accessible 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) (accessible 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. Examples of moderate CYP3A4 inhibitors include fluconazole, amiodarone, erythromycin, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan, chamomile, licorice, cherry blossom, echinacea angustifolia, fluvoxamine, aprepitant, ciprofloxacin, crizotinib, cyclosporine, dronedarone, imatinib, isavuconazole, and tofisofam. Examples of weak CYP3A4 inhibitors include cimetidine, chlorzoxazone, cilostazol, clotrimazole, fosaprepitant, istradefylline, ivacaftor, lomitapide, ranitidine, ranolazine, and ticagrelor.

[0050] As used herein, the term "pharmaceutically acceptable excipient" includes any of the standard pharmaceutical excipients, including carriers such as phosphate-buffered saline, water, and emulsions (e.g., oil / water emulsions or water / oil emulsions), as well as various types of wetting agents. Pharmaceutical compositions may also include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).

[0051] As used herein, the term "pharmaceutically acceptable salt" means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a compound of the present disclosure, which may be administered without any substantial undesired biological effects or adverse interactions with any other components of the pharmaceutical composition it may contain.

[0052] Addition salts can be readily prepared using conventional techniques, for example, by treating the base compound with a predetermined amount of a selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as, for example, methanol or ethanol. Positively charged compounds (e.g., quaternary ammonium-containing compounds) can also form salts with the anionic components of various inorganic and / or organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts are those that can form non-toxic acid addition salts, for example, salts with pharmaceutically 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. The bases that can be used to prepare pharmaceutically acceptable base addition salts can form non-toxic base addition salts, for example, salts containing pharmaceutically 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 (e.g., N-methylglucamine (meglumine)), lower alkanolammonium, and other such bases of organic amines. The addition salt of benglustat is typically an acid addition salt. In an embodiment, the pharmaceutically acceptable salt of benglustat is benglustat malate, particularly benglustat L-malate.

[0053] The mass of benglustat referred to herein corresponds to the mass of benglustat calculated as the free base, unless otherwise specified. For example, a "15 mg dose of benglustat" refers to the amount of a salt or prodrug of benglustat that provides 15 mg of benglustat free base or an equivalent molar amount (e.g., 20 mg of benglustat malate). Thus, references to "benglustat" throughout this specification include pharmaceutically acceptable salts and prodrugs of benglustat, for example, as described herein.

[0054] The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiment or portion thereof.

[0055] Any composition or method provided herein can be combined with one or more of any of the other compositions and methods provided herein.

[0056] The following abbreviations are used herein: Aβ amyloid beta ADAM Advanced Solubility, Absorption and Metabolism ADME Absorption, Distribution, Metabolism and Excretion ADPKD Autosomal dominant polycystic kidney disease AGP alpha-1 acid glycoprotein ARPKD Autosomal recessive polycystic kidney disease AUC Area under the plasma concentration-time curve AUC 0-12 12 hours AUC(AUC 0-24 =24 hours AUC) AUC inf Area under the plasma concentration-time curve (AUC ∞ too) AUC last 0 to t last Area under the plasma concentration-time curve of AUC tau Area under the plasma concentration-time curve over the dosing interval BBS Bardet-Biedl syndrome B / P Blood-to-Plasma Ratio BID twice a day (administration) CDI Carbonyldiimidazole C max Maximum observed plasma concentration C trough Plasma concentration just before TP2 CL / F Apparent total body clearance from plasma CL int Intrinsic Clearance CL int-CYP2D6 Intrinsic metabolic clearance assigned to CYP2D6 CL int-CYP3A4 Intrinsic metabolic clearance assigned to CYP3A4 CL r Renal clearance CL uG,int Intrinsic gut clearance CYP cytochrome P450 (or cytochrome oxidase P450) DDI Drug-drug interactions DMF Dimethylformamide DNA deoxyribonucleic acid EDTA Ethylenediaminetetraacetic acid f a Absorption fraction F g intestinal availability f m partial metabolism f u,gut Unbound fraction in the intestine f u,mic Percent unbound human liver microsomal protein f u,p Unbound fraction in plasma fe 0-24 24-hour unchanged urinary excretion rate GCS glucosylceramide synthase GD Gaucher disease GI gastrointestinal GM1 monosialotetrahexosylganglioside GM2 monosialotrihexosylganglioside Hex β-hexosaminidase HIV human immunodeficiency virus HCV Hepatitis C virus HLM Human Liver Microsomes HPC Hydroxypropyl Cellulose HPLC High Pressure / High Performance Liquid Chromatography HSA Human serum albumin IPA Isopropyl Alcohol K a First-order absorption rate constant K i Inhibition constant LC / MS Liquid Chromatography Mass Spectrometry MDCKII Madin-Darby canine kidney line II MDR1 multidrug resistance mutation 1 MS mass spectrometry obs observed values OH-Itraconazole Hydroxyitraconazole P app Apparent Permeability Coefficient P eff,man Estimated in vivo permeability PBPK Physiologically Based Pharmacokinetics Pgp P-glycoprotein PK Pharmacokinetics PKD Polycystic Kidney Disease POPPK Population Pharmacokinetics pred predicted value QD: Repeated once daily (administration) QS quantum satis - enough to supplement the intended amount RB round bottom rHA Recombinant Human Albumin RNA ribonucleic acid SAC Single Adjustment Compartment SAE serious adverse event SD single dose t 1 / 2 Half-life t 1 / 2z Terminal half-life related to terminal gradient last Time of last administration t max Peak concentration (C max ) TBME tert-butyl methyl ether TEAE Treatment-emergent adverse events THF tetrahydrofuran TID 3 times a day (administration) TP1 Treatment Period 1 TP2 Treatment period 2 Tris Tris(hydroxymethyl)aminomethane TWEEN 20 Polysorbate 20 TWEEN 80 Polysorbate 80 Wt.% Weight percent UPLCMS Ultra High Performance Liquid Chromatography Mass Spectrometry V ss Apparent volume of distribution at steady state

[0057] Coadministration of benglustat with a CYP3A4 inhibitor Benglestat (free base) has the chemical structure according to formula (I) below and can be conveniently provided in the form of a malic acid addition salt (prepared, for example, as described in the Examples below). [ka]

[0058] Benglustat is an oral GCS inhibitor in development for the treatment of Fabry disease, Gaucher disease, and GM2 gangliosidosis. Benglustat is primarily metabolized by CYP3A4.

[0059] Several CYP3A4 inhibitors, including the strong CYP3A4 inhibitor itraconazole and the moderate CYP3A4 inhibitors fluconazole and fluvoxamine, are evaluated in the following examples. Itraconazole is an antifungal agent that has also been studied as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer. It is also being studied for use in combination with other chemotherapy agents for advanced and metastatic basal cell carcinoma that cannot be treated surgically. Itraconazole can be administered orally, topically, or intravenously. For oral administration, it is typically formulated as a tablet or capsule containing approximately 100 mg of active substance per dose. Fluconazole is another antifungal agent. It can be administered orally or intravenously, with typical dosages ranging from 100 mg to 400 mg daily. Fluvoxamine is a selective serotonin reuptake inhibitor with 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 at doses starting at 50-100 mg daily, which can be increased to about 300 mg daily as needed.

[0060] This disclosure and the following examples describe the development and validation of a physiologically based pharmacokinetic (PBPK) model to evaluate the effect of a CYP3A4 inhibitor on benglustat pharmacokinetics. The clinical studies and subsequent modeling described herein establish, for the first time, a quantitative relationship between in vivo CYP3A4 inhibition and changes in benglustat plasma exposure. Based on the studies described herein, the present disclosure therefore provides a dosing regimen for benglustat treatment in patients co-administered with a CYP3A4 inhibitor. In particular, the present disclosure provides a validated approach for accounting for co-administration of moderate or strong CYP3A4 inhibitors with benglustat, thereby enabling safe and effective treatment in these patient populations. The modeling described herein can be extended to determine the impact of CYP3A4 inducers on benglustat pharmacokinetics, enabling similar evaluations to be performed to optimize benglustat dosing in patients co-administered with a CYP3A4 inducer, for example.

[0061] Thus, in one aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of benglustat or a pharmaceutically acceptable salt thereof to the subject, wherein the subject is concomitantly receiving a strong or moderate inhibitor of CYP3A4. In a related aspect, the present disclosure provides benglustat or a pharmaceutically acceptable salt thereof for use in a method of treating a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of benglustat or a pharmaceutically acceptable salt thereof to the subject, wherein the subject is concomitantly receiving a strong or moderate inhibitor of CYP3A4. A further related aspect provides the use of benglustat in the manufacture of a medicament for use in a method of treating a disease or disorder in a subject in need thereof, the method comprising administering an effective amount of benglustat to the subject and concomitantly administering a strong or moderate inhibitor of CYP3A4.

[0062] In another aspect, the disclosure provides a method of 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 benglustat or a pharmaceutically acceptable salt thereof and a strong or moderate inhibitor of CYP3A4 (e.g., a composition comprising them). In a related aspect, the disclosure provides a combination of benglustat or a pharmaceutically acceptable salt thereof and a strong or moderate inhibitor of CYP3A4 (e.g., a composition comprising them) for use in a method of treating a disease or disorder in a subject in need thereof. A further related aspect provides the use of benglustat 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 of treating a disease or disorder in a subject in need thereof.

[0063] In embodiments, the strong or moderate inhibitor of CYP3A4 is a competitive inhibitor of CYP3A4. In embodiments, one or more metabolites of a strong or moderate inhibitor of CYP3A4 may inhibit CYP3A4, such that, for example, the strong or moderate inhibitor can increase benglustat exposure through mechanism-based inhibition. In embodiments, the strong or moderate inhibitor of CYP3A4 is a triazole antifungal agent, such as itraconazole or fluconazole.

[0064] The present disclosure also provides a method for treating a disease or disorder in a subject in need thereof, comprising administering an effective amount of benglustat or a pharmaceutically acceptable salt thereof to the subject, wherein the subject is concurrently administered an inhibitor of CYP3A4, whereby the plasma exposure (e.g., AUC) of benglustat is increased by at least about 25% compared to the exposure resulting from administration of the same dosage form, form and regimen of benglustat or a pharmaceutically acceptable salt thereof in the absence of the CYP3A4 inhibitor. In a related aspect, the present disclosure provides benglustat 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 an effective amount of benglustat or a pharmaceutically acceptable salt thereof to the subject, wherein the subject is concurrently administered an inhibitor of CYP3A4, whereby the plasma exposure (e.g., AUC) of benglustat is increased by at least about 25% compared to the exposure resulting from administration of benglustat or a pharmaceutically acceptable salt thereof in the same dosage form, form and regimen in the absence of said CYP3A4 inhibitor. A further related aspect provides the use of benglustat 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 in need thereof, the method comprising administering an effective amount of benglustat or a pharmaceutically acceptable salt thereof to a subject, the subject being concomitantly administered a CYP3A4 inhibitor, whereby the plasma exposure (e.g., AUC) of benglustat is increased by at least about 25% compared to the exposure resulting from administration of benglustat or a pharmaceutically acceptable salt thereof in the same dosage form, form, and regimen in the absence of said CYP3A4 inhibitor. Methods for determining increased plasma exposure of a CYP3A4 inhibitor are described herein, including in detail in the Examples below.

[0065] In another aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a combination of benglustat or a pharmaceutically acceptable salt thereof and an inhibitor of CYP3A4 (e.g., a composition comprising them), whereby the plasma exposure (e.g., AUC) of benglustat is increased by at least about 25% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof in the same dosage form, form, and regimen in the absence of the CYP3A4 inhibitor. In a related aspect, the present disclosure provides a combination of benglustat or a pharmaceutically acceptable salt thereof and an inhibitor of CYP3A4 (e.g., a composition comprising them) for use in a method of treating a disease or disorder in a subject in need thereof, whereby the plasma exposure (e.g., AUC) of benglustat is increased by at least about 25% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof in the same dosage form, form, and regimen in the absence of the CYP3A4 inhibitor. A further related aspect provides the use of benglustat or a pharmaceutically acceptable salt thereof and an inhibitor of CYP3A4 in the manufacture of a medicament for use in a method of treating a disease or disorder in a subject in need thereof, whereby the plasma exposure (e.g., AUC) of benglustat is increased by at least about 25% compared to the exposure resulting from administration of benglustat or a pharmaceutically acceptable salt thereof in the same dosage form, form and regimen in the absence of the CYP3A4 inhibitor.

[0066] In the foregoing aspects of the disclosure, the disease or disorder is amenable to treatment with benglustat (or a pharmaceutically acceptable salt thereof). Exemplary diseases and disorders treatable with benglustat are described herein.

[0067] In embodiments, the plasma exposure of benglustat is measured by the AUC of benglustat, e.g., AUC 0-12 , AUC 0-24 , AUC last or AUC ∞In embodiments, the plasma exposure of benglustat is determined by the AUC last In embodiments, the plasma exposure of benglustat is measured experimentally. In other embodiments, the plasma exposure of benglustat is estimated by modeling, such as the modeling described herein.

[0068] In embodiments, benglustat or a pharmaceutically acceptable salt thereof and a 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). In other embodiments, benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor are administered in combination, e.g., in the same pharmaceutical composition.

[0069] In embodiments, the CYP3A4 inhibitor is a potent inhibitor. In embodiments, the inhibitor increases the plasma exposure of benglustat by at least about 50% compared to the exposure resulting from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dose, form, and regimen in the absence of said CYP3A4 inhibitor. In embodiments, a potent inhibitor increases the plasma exposure of benglustat by at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 88%, 90%, 92%, 95%, 98%, or 100% compared to the exposure resulting from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dose, form, and regimen in the absence of said CYP3A4 inhibitor. In embodiments, a strong inhibitor increases the plasma exposure of benglustat by about 50% to 400%, e.g., about 55% to 300%, about 60% to 200%, or about 65% to 150%, compared to the exposure resulting from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dose, form, and regimen in the absence of said CYP3A4 inhibitor.

[0070] In embodiments, the potent inhibitor increases the plasma exposure of benglustat by about 50% to 150% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage that is about 25% to 100% of the standard prescribed dose for the disease or disorder being treated (e.g., about 50% to 100% of the standard prescribed dose). In embodiments, the potent inhibitor increases the plasma exposure of benglustat by about 60% to 90% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage that is 100% of the standard prescribed dose for the disease or disorder being treated. In another embodiment, the potent inhibitor increases the plasma exposure of benglustat by about 90% to 120% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage that is about 50% to 75% of the standard indicated dose for the disease or disorder being treated. In another embodiment, the potent inhibitor increases the plasma exposure of benglustat by about 60% to 150% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 4 mg to 15 mg / day (calculated as the free base), for example, about 8 mg to 12 mg / day (calculated as the free base).

[0071] In an embodiment, the CYP3A4 inhibitor is a potent inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 8 mg / day (calculated as the free base), e.g., about 7.0 mg to about 9.0 mg / day, e.g., about 7.5 mg or about 8.0 mg (calculated as the free base). A dosage of about 7.5 mg can be obtained, for example, by dividing a 15 mg tablet in half. A dosage of about 8.0 mg can be obtained, for example, by administering two 4 mg unit doses (e.g., tablets or capsules). In another embodiment, the CYP3A4 inhibitor is a potent inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 15 mg / day (calculated as the free base). In an embodiment, the potent inhibitor is itraconazole administered at a dosage of about 50 mg to 400 mg / day, e.g., about 200 mg / day (e.g., a dosage of about 100 mg BID).

[0072] In another embodiment, the CYP3A4 inhibitor is a moderate inhibitor of CYP3A4. In embodiments, the inhibitor increases the plasma exposure of benglustat by about 5% to 25% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dose, form, and regimen in the absence of said CYP3A4 inhibitor. In another embodiment, the inhibitor increases the plasma exposure of benglustat by at least about 25% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dose, form, and regimen in the absence of said CYP3A4 inhibitor. In embodiments, a moderate inhibitor increases the plasma exposure of benglustat by about 25% to 75%, e.g., about 30% to 65%, about 35% to 60%, or about 40% to 55%, compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dose, form, and regimen in the absence of said CYP3A4 inhibitor.

[0073] In embodiments, a moderate inhibitor increases the plasma exposure of benglustat by about 5% to 20% compared to the exposure resulting from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage that is 100% of the standard prescribed dose for the disease or disorder being treated. In embodiments, benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 15 mg / day (calculated as the free base). In another embodiment, a moderate inhibitor increases the plasma exposure of benglustat by about 30% to 65% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage that is about 75% to 100% of the standard prescribed dose for the disease or disorder being treated. In an embodiment, a moderate inhibitor increases the plasma exposure of benglustat by about 40% to 60% compared to the exposure that would result from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage that is 100% of the standard prescribed dose for the disease or disorder being treated. In another embodiment, a moderate inhibitor increases the plasma exposure of benglustat by about 40% to 60% compared to the exposure resulting from administration of benglustat or a pharmaceutically acceptable salt thereof at the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg to 15 mg / day (calculated as the free base), e.g., about 12 mg / day or about 15 mg / day. In an embodiment, the CYP3A4 inhibitor is a moderate inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dose of about 12 mg / day (calculated as the free base).In another embodiment, the CYP3A4 inhibitor is a moderate inhibitor, and benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 15 mg / day (calculated as the free base). A dosage of about 12 mg can be achieved, for example, by administering three 4 mg unit doses (e.g., tablets or capsules) or two 6 mg unit doses (e.g., tablets or capsules). A dosage of about 10 mg can be achieved, for example, by administering one 4 mg unit dose (e.g., tablet or capsule) and one 6 mg unit dose (e.g., tablet or capsule).

[0074] In embodiments, the CYP3A4 inhibitor is fluconazole administered at a dose of about 100 mg to 500 mg per day, e.g., about 200 mg or about 400 mg per day. In embodiments, the CYP3A4 inhibitor is fluvoxamine administered at a dose of about 50 mg to 300 mg per day. In other embodiments, the CYP3A4 inhibitor is not fluvoxamine. In embodiments, the CYP3A4 inhibitor is not cyclosporine. In embodiments, the CYP3A4 inhibitor is not fluvoxamine or cyclosporine.

[0075] In embodiments, the disclosed methods comprise administering an effective amount of benglustat or a pharmaceutically acceptable salt thereof to a subject, where the subject is concurrently receiving a CYP3A4 inhibitor selected from itraconazole and fluconazole. In other embodiments, the disclosed methods comprise administering to a subject an effective amount of benglustat or a pharmaceutically acceptable salt thereof in combination with (e.g., a composition comprising) a CYP3A4 inhibitor selected from itraconazole and fluconazole. In a related aspect, the disclosure provides a combination of (e.g., a composition comprising) benglustat or a pharmaceutically acceptable salt thereof in combination with (e.g., a composition comprising) a CYP3A4 inhibitor selected from itraconazole and fluconazole for use in a method of treating a disease or disorder amenable to treatment with benglustat in a subject in need thereof. A further related aspect provides the use of benglustat 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 of treating a disease or disorder amenable to treatment with benglustat in a subject in need thereof.

[0076] In an embodiment, benglustat is in the form of benglustat free base, a pharmaceutically acceptable salt of benglustat or a prodrug of benglustat. In one embodiment, benglustat is in the form of benglustat malate, e.g., benglustat L-malate, optionally in crystalline form.

[0077] In embodiments, benglustat or a pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered simultaneously, optionally in the same pharmaceutical composition (e.g., an oral pharmaceutical dosage form).

[0078] In embodiments, benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor are administered separately. In embodiments, the method comprises administering a separate pharmaceutical composition comprising a CYP3A4 inhibitor (i.e., separate from a pharmaceutical composition or dosage form comprising benglustat or a pharmaceutically acceptable salt thereof).

[0079] In embodiments, benglustat or a pharmaceutically acceptable salt thereof is administered orally. In embodiments, the CYP3A4 inhibitor is administered orally. In embodiments, benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor are administered orally.

[0080] In other embodiments, the CYP3A4 inhibitor is administered transdermally, transmucosally, intravenously, intramuscularly, subcutaneously, or intranasally. In embodiments, the CYP3A4 inhibitor is administered transmucosally, intravenously, or orally. In embodiments, the CYP3A4 inhibitor is administered transdermally, transmucosally, intravenously, intramuscularly, subcutaneously, or intranasally, and benglustat or a pharmaceutically acceptable salt thereof is administered orally. In embodiments, benglustat or a pharmaceutically acceptable salt thereof is administered orally, and the CYP3A4 inhibitor is administered transmucosally, intravenously, or orally.

[0081] In embodiments, benglustat or a pharmaceutically acceptable salt thereof (and optionally a CYP3A4 inhibitor) is formulated as an oral pharmaceutical composition. In embodiments, the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient described herein. In embodiments, the pharmaceutical composition further comprises a CYP3A4 inhibitor.

[0082] In embodiments, the oral pharmaceutical composition is a pill, capsule, caplet, tablet, dragee, powder, granule, film, lozenge, or liquid. In embodiments, the oral pharmaceutical composition is a capsule or tablet, e.g., a tablet. In one embodiment, the oral pharmaceutical composition is a formulation described in International Patent Application No. PCT / IB2021 / 056673 (published as WO 2022 / 018695), the entire contents of which are incorporated herein by reference.

[0083] In embodiments, the formulation is a capsule having the following composition:

[0084] [Table 1]

[0085] In an embodiment, the capsule contains 15 mg of benglustat (20.16 mg of benglustat malate), the capsule fill mass is 165 mg, and the formulation is packaged in a size #3 capsule shell.

[0086] In another embodiment, the formulation is a tablet having the following composition:

[0087] [Table 2]

[0088] In an embodiment, the tablet contains 15 mg of benglustat (20.16 mg of benglustat malate), the flavor is apricot flavor, the sweetener is sucralose, and the tablet weighs 150 mg.

[0089] In one embodiment, the CYP3A4 inhibitor is itraconazole. In another embodiment, the CYP3A4 inhibitor is fluconazole.

[0090] In embodiments, the disease or disorder is selected from a lysosomal storage disease, a proteinopathy, a cystic disease, and a ciliopathy.

[0091] In several embodiments, the disease or disorder is a lysosomal storage disorder selected from Fabry disease, Gaucher disease (e.g., GD1, 2, or 3), GM1-gangliosidosis, 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. In embodiments, the disease or disorder is Gaucher disease or Fabry disease. In one embodiment, the disease or disorder is Gaucher disease type 3 (GD3).

[0092] In embodiments, the disease or disorder is a proteinopathy selected from Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, Pick's disease, progressive supranuclear palsy, pugilicin dementia, chromosome 17-linked parkinsonism, Lytico-Bodig disease, oblique-predominant dementia, argyrophilic grain disease, ganglioneuroma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Haller-Boden-Spatz disease, fatty liver disease, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, and Huntington's disease. In embodiments, 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, α-synuclein protein aggregates, and / or amyloid-β (Aβ) aggregates in the central nervous system.

[0093] In embodiments, the disease or disorder is a cystic disease selected from polycystic kidney disease, polycystic liver disease, and polycystic ovarian disease. In embodiments, the cystic disease is polycystic kidney disease (PKD), such as autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD).

[0094] In embodiments, the disease or disorder is a ciliopathy selected from Joulet syndrome, Meckel-Gruber syndrome, Senryo-Loken syndrome, Orofaci-Ditar syndrome type I, Leber congenital amaurosis, Bardet-Biedl syndrome (BBS), Alström syndrome, Genet asphyxiating thoracic dystrophy, Ellis-van Creveld syndrome, Sensenbrenner syndrome, primary ciliary dyskinesia, and combinations thereof. In embodiments, the ciliopathy is BBS.

[0095] In embodiments, the subject has a comorbid condition that can be treated with the CYP3A4 inhibitor, in embodiments, the comorbid condition 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 anxiety disorder), and cancer.

[0096] Dose adjustment As described herein, co-administration of benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor can increase the plasma exposure (e.g., AUC) of benglustat, for example, by about 50% to about 200%, which may allow for the use of adjusted (e.g., lower) doses of benglustat compared to the standard indicated dose for the disease or disorder being treated.

[0097] Thus, in a further aspect, the present disclosure provides a method of treating a disease or disorder amenable to treatment with benglustat in a subject in need thereof, the method comprising administering a strong or moderate CYP3A4 inhibitor to the subject and simultaneously administering a controlled effective amount of benglustat or a pharmaceutically acceptable salt thereof. In a related aspect, the present disclosure provides benglustat or a pharmaceutically acceptable salt thereof for use in a method of treating a disease or disorder amenable to treatment with benglustat in a subject in need thereof, the method comprising administering a strong or moderate CYP3A4 inhibitor to the subject and simultaneously administering a controlled effective amount of benglustat or a pharmaceutically acceptable salt thereof. In another related aspect, the present disclosure provides the use of benglustat 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, the method comprising simultaneously administering a CYP3A4 inhibitor and the amount of benglustat or a pharmaceutically acceptable salt thereof in the medicament being a controlled effective amount. In embodiments, the CYP3A4 inhibitor is selected from itraconazole and fluconazole. In embodiments, the CYP3A4 inhibitor is not fluvoxamine.

[0098] In another aspect, the disclosure provides a method of treating a disease or disorder amenable to treatment with benglustat in a subject in need thereof, the method comprising administering to the subject a combination (e.g., a composition) of a strong or moderate CYP3A4 inhibitor and benglustat or a pharmaceutically acceptable salt thereof, wherein the benglustat or a pharmaceutically acceptable salt thereof is administered in a controlled effective amount. In a related aspect, the disclosure provides a combination (e.g., a composition comprising) benglustat or a pharmaceutically acceptable salt thereof and a strong or moderate CYP3A4 inhibitor for use in a method of treating a disease or disorder amenable to treatment with benglustat in a subject in need thereof, the method comprising administering to the subject a controlled effective amount of benglustat or a pharmaceutically acceptable salt thereof. In another related aspect, the present disclosure provides use of a combination (e.g., a composition comprising) benglustat or a pharmaceutically acceptable salt thereof and a strong or moderate CYP3A4 inhibitor in the manufacture of a medicament for use in a method for treating a disease or disorder in a subject that is suitable for treatment with benglustat, wherein the amount of benglustat or a pharmaceutically acceptable salt thereof in the medicament is an adjusted effective amount. In embodiments, the CYP3A4 inhibitor is selected from itraconazole and fluconazole. In embodiments, the CYP3A4 inhibitor is not fluvoxamine.

[0099] In embodiments, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 25% to 100% of the standard prescribed dose for the disease or disorder being treated (e.g., about 50% to 100% of the standard prescribed dose). In embodiments, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is at least about 50% of the standard prescribed 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 prescribed dose. In embodiments, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is less than 100% of the standard prescribed 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 prescribed dose. In an embodiment, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 50% to about 99% of the standard prescribed dose for the disease or disorder being treated, e.g., about 55% to about 95%, about 60% to about 90%, or about 65% to about 75% of the standard prescribed dose. In an embodiment, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 50% of the standard prescribed dose for the disease or disorder being treated, e.g., about 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90% of the standard prescribed dose.

[0100] In one embodiment, the CYP3A4 inhibitor is a potent inhibitor (e.g., itraconazole), and the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 50% to 100% of the standard prescribed dose for the disease or disorder being treated. In another embodiment, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is 100% of the standard prescribed dose for the disease or disorder being treated (e.g., a dose of about 15 mg / day). In another embodiment, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 50% to 100% of the standard prescribed dose for the disease or disorder being treated, for example, about 50% to about 90%, about 50% to about 80%, about 50% to about 70%, or about 50% to about 60% of the standard prescribed dose. In an embodiment, the standard prescribed dose of benglustat or a pharmaceutically acceptable salt thereof is about 15 mg / day (calculated as the free base), and the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 8 mg / day (calculated as the free base), e.g., about 7.0 mg to about 9.0 mg / day, e.g., about 7.5 mg or about 8.0 mg (calculated as the free base). A dose of about 7.5 mg can be obtained, for example, by dividing a 15 mg tablet in half. A dose of about 8.0 mg can be achieved, for example, by administering two 4 mg unit doses (e.g., tablets or capsules).

[0101] In another embodiment, the CYP3A4 inhibitor is a moderate inhibitor (e.g., fluconazole), and the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 70% to 100% of the standard prescribed dose for the disease or disorder being treated. In an embodiment, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is 100% of the standard prescribed dose for the disease or disorder being treated. In another embodiment, the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 75% to 100% of the standard prescribed dose for the disease or disorder being treated, e.g., about 80% to 100%, about 85% to 100%, about 90% to 100%, or about 95% to 100% of the standard prescribed dose. In embodiments, the standard prescribed dose of benglustat is about 15 mg / day, and the adjusted effective amount of benglustat or a pharmaceutically acceptable salt thereof is about 10 mg to 15 mg / day, e.g., about 12 mg / day or about 15 mg / day (calculated as the free base). A dosage of about 12 mg can be achieved, for example, by administering three 4 mg unit doses (e.g., tablets or capsules) or two 6 mg unit doses (e.g., tablets or capsules). A dosage of about 10 mg can be achieved, for example, by administering one 4 mg unit dose (e.g., tablet or capsule) and one 6 mg unit dose (e.g., tablet or capsule).

[0102] In embodiments, benglustat or a pharmaceutically acceptable salt thereof and / or the CYP3A4 inhibitor is as defined herein.

[0103] In embodiments, the subject to be treated and / or the disease or disorder to be treated is as defined herein.

[0104] In a further aspect, the present disclosure provides a method of optimizing (e.g., reducing) the dosage of benglustat in a subject being treated or intended to be treated with benglustat or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject a strong or moderate CYP3A4 inhibitor, e.g., as defined herein. In embodiments, the strong or moderate CYP3A4 inhibitor is administered simultaneously with benglustat or a pharmaceutically acceptable salt thereof. In a related aspect, the present disclosure provides a strong or moderate CYP3A4 inhibitor, e.g., as defined herein, for use in a method of optimizing (e.g., reducing) the dosage of benglustat in a subject being treated or intended to be treated with benglustat or a pharmaceutically acceptable salt thereof. In a further aspect, the present disclosure provides the use of a strong or moderate CYP3A4 inhibitor, such as a CYP3A4 inhibitor as defined herein, in the manufacture of a medicament for use in a method for optimizing (e.g., reducing) the dosage of benglustat in a subject being treated or intended to be treated with benglustat or a pharmaceutically acceptable salt thereof. In an embodiment, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In an embodiment, the CYP3A4 inhibitor is selected from itraconazole and fluconazole.

[0105] In another aspect, the present disclosure provides a method of minimizing a drug-drug interaction between benglustat and a moderate or strong CYP3A4 inhibitor in a subject suffering from a disease or disorder amenable to treatment with benglustat (e.g., as defined herein) or a pharmaceutically acceptable salt thereof, the method comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with said CYP3A4 inhibitor compared to the exposure that would result from administration of benglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) adjusting the dosage of benglustat or a pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

[0106] In embodiments, determining the change in plasma exposure of benglustat comprises, for example, measuring the change in plasma exposure after administration of benglustat and / or a CYP3A4 inhibitor in one or more healthy subjects. In other embodiments, determining the change in plasma exposure of benglustat comprises predicting the change in plasma exposure, for example, using a computer-implemented model described herein. In embodiments, plasma exposure is determined as AUC, as defined herein. In embodiments, AUC is AUC 0-12 , AUC 0-24 , AUC last or AUC ∞ In embodiments, the plasma exposure of benglustat is determined by the AUC last is.

[0107] In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor, and / or if the change in plasma exposure is an increase of more than about 50%, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced. In embodiments, the reduced dose is an adjusted effective amount as defined herein. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor, and if the change in plasma exposure is an increase of about 0% to 75%, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced by an amount of about 50% to 200% (e.g., about 0% to 50%). In embodiments, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced by an amount of about 5% to 50%, e.g., about 10% to 50%, about 25% to 50%, or about 40% to 50%. In an embodiment, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced to about 4 to 15 mg / day (calculated as the free base) if the change in plasma exposure is about a 50% to 200% increase, e.g., to about 7 to 15 mg / day if the change in plasma exposure is about a 50% to 200% increase. In an embodiment, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced to about 8 mg / day (calculated as the free base), e.g., about 7.0 to about 9.0 mg / day, e.g., about 7.5 mg or about 8.0 mg (calculated as the free base). A dose of about 7.5 mg can be obtained, for example, by splitting a 15 mg tablet in half. A dose of about 8.0 mg can be achieved, for example, by administering two 4 mg unit doses (e.g., tablets or capsules).

[0108] In another aspect, the present disclosure provides a method for establishing the correct dosage of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, the method comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor compared to the exposure that would result from administration of benglustat in the same dosage, form and regimen in the absence of said CYP3A4 inhibitor; and (ii) reducing the dosage of benglustat or a pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

[0109] In a related aspect, the present disclosure provides a method for improving the dosing regimen of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, the method comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor compared to the exposure resulting from administration of benglustat in the same dosage, form and regimen in the absence of said CYP3A4 inhibitor; and (ii) reducing the dosage of benglustat or a pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

[0110] In embodiments, determining the change in plasma exposure of benglustat comprises, for example, measuring the change in plasma exposure after administration of benglustat and / or a CYP3A4 inhibitor in one or more healthy subjects. In other embodiments, determining the change in plasma exposure of benglustat comprises predicting the change in plasma exposure, for example, using a computer-implemented model described herein. In embodiments, plasma exposure is determined as AUC, as defined herein. In embodiments, AUC is AUC 0-12 , AUC 0-24 , AUC last or AUC ∞ In embodiments, the plasma exposure of benglustat is determined by the AUC last is.

[0111] In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor, and / or if the change in plasma exposure is an increase of more than about 50%, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced. In embodiments, the reduced dose is an adjusted effective amount as defined herein. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor, and if the change in plasma exposure is an increase of about 50% to 200%, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced by an amount of about 0% to 50%. In embodiments, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced by an amount of about 5% to 50%, e.g., about 10% to 50%, about 25% to 50%, or about 40% to 50%. In an embodiment, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced to about 4 to 15 mg / day (calculated as the free base) if the change in plasma exposure is about a 50% to 200% increase, e.g., to about 7 to 15 mg / day if the change in plasma exposure is about a 50% to 200% increase. In an embodiment, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced to about 8 mg / day (calculated as the free base), e.g., about 7.0 to about 9.0 mg / day, e.g., about 7.5 mg or about 8.0 mg (calculated as the free base). A dose of about 7.5 mg can be obtained, for example, by splitting a 15 mg tablet in half. A dose of about 8.0 mg can be achieved, for example, by administering two 4 mg unit doses (e.g., tablets or capsules).

[0112] Another aspect of the present disclosure provides a method of managing the risk of benglustat / CYP3A4 inhibitor interaction in a subject having a disease or disorder amenable to treatment with benglustat or a pharmaceutically acceptable salt thereof, the method comprising: (i) initiating treatment in the subject with benglustat or a pharmaceutically acceptable salt thereof at a standard prescribed dose (e.g., a dose described herein); (ii) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor compared to the exposure that would result from administration of benglustat 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%.

[0113] In embodiments, determining the change in plasma exposure of benglustat comprises, for example, measuring the change in plasma exposure after administration of benglustat and / or a CYP3A4 inhibitor in one or more healthy subjects. In other embodiments, determining the change in plasma exposure of benglustat comprises predicting the change in plasma exposure, for example, using a computer-implemented model described herein. In embodiments, plasma exposure is determined as AUC, as defined herein. In embodiments, AUC is AUC 0-12 , AUC 0-24 , AUC last or AUC ∞ In embodiments, the plasma exposure of benglustat is determined by the AUC last is.

[0114] In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor, and / or if the change in plasma exposure is an increase of more than about 50%, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced. In embodiments, the reduced dose is an adjusted effective amount as defined herein. In embodiments, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor, and if the change in plasma exposure is an increase of about 50% to 200%, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced by an amount of about 0% to 50%. In embodiments, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced by an amount of about 5% to 50%, e.g., about 10% to 50%, about 25% to 50%, or about 40% to 50%. In an embodiment, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced to about 4 to 15 mg / day (calculated as the free base) if the change in plasma exposure is about a 50% to 200% increase, e.g., to about 7 to 15 mg / day if the change in plasma exposure is about a 50% to 200% increase. In an embodiment, the dose of benglustat or a pharmaceutically acceptable salt thereof is reduced to about 8 mg / day (calculated as the free base), e.g., about 7.0 to about 9.0 mg / day, e.g., about 7.5 mg or about 8.0 mg (calculated as the free base). A dose of about 7.5 mg can be obtained, for example, by splitting a 15 mg tablet in half. A dose of about 8.0 mg can be achieved, for example, by administering two 4 mg unit doses (e.g., tablets or capsules).

[0115] In another aspect, the present disclosure also provides the use of a strong or moderate CYP3A4 inhibitor in a method for (a) establishing the correct dosage of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, (b) improving the dosing regimen of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, or (c) managing the risk of a benglustat / CYP3A4 inhibitor interaction in a subject having a disease or disorder amenable to treatment with benglustat or a pharmaceutically acceptable salt thereof, wherein the subject is receiving or is intended to be receiving said CYP3A4 inhibitor. In an embodiment, the method is a method described herein.

[0116] Other methods In another aspect, the present disclosure provides a method for inhibiting CYP3A4 activity in a subject being treated with benglustat or a pharmaceutically acceptable salt thereof, the method comprising administering benglustat or a pharmaceutically acceptable salt thereof concomitantly with a strong or moderate CYP3A4 inhibitor. In a related aspect, 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 benglustat or a pharmaceutically acceptable salt thereof, the method comprising administering benglustat or a pharmaceutically acceptable salt thereof concomitantly with a CYP3A4 inhibitor. In a further aspect, 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 benglustat or a pharmaceutically acceptable salt thereof. In an embodiment, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In an embodiment, the CYP3A4 inhibitor is selected from itraconazole and fluconazole. In an embodiment, the CYP3A4 inhibitor is not fluvoxamine.

[0117] In another aspect, the present disclosure provides a method of improving the therapeutic response to benglustat treatment in a subject in need thereof, the method comprising administering benglustat or a pharmaceutically acceptable salt thereof concomitantly with a strong or moderate CYP3A4 inhibitor. In a related aspect, the present disclosure provides a strong or moderate CYP3A4 inhibitor for use in a method of improving the therapeutic response to benglustat treatment in a subject in need thereof. In a further aspect, 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 benglustat treatment in a subject in need thereof. In an embodiment, the CYP3A4 inhibitor is a strong CYP3A4 inhibitor. In an embodiment, the CYP3A4 inhibitor is selected from itraconazole and fluconazole. In an embodiment, the CYP3A4 inhibitor is not fluvoxamine.

[0118] In embodiments, benglustat or a pharmaceutically acceptable salt thereof and / or the CYP3A4 inhibitor is as defined herein.

[0119] In embodiments, co-administration of benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor allows for the use of a lower dose of benglustat or a pharmaceutically acceptable salt thereof compared to the standard prescribed dose for the disease or disorder being treated, in embodiments, the lower dose of benglustat or a pharmaceutically acceptable salt thereof is an adjusted effective amount as described herein.

[0120] In embodiments, co-administration of benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor results in an increase in the plasma AUC of benglustat of at least about 25% compared to the plasma AUC that would result from administration of benglustat or a pharmaceutically acceptable salt thereof in the absence of the CYP3A4 inhibitor.

[0121] In embodiments, the subject is being treated for a disease or disorder as defined herein.

[0122] In various aspects and embodiments of the present disclosure, the change in plasma exposure of benglustat upon co-administration of a strong or moderate CYP3A4 inhibitor is determined by computer-implemented methods, for example, as described in the Examples below.

[0123] Forms of benglustat The present disclosure contemplates salt forms of benglustat, for example, benglustat in the form of a pharmaceutically acceptable salt.

[0124] Compounds that are basic in nature can generally form a wide variety of different salts with various inorganic and / or organic acids. While such salts are generally pharmaceutically acceptable for administration to animals and humans, in practice it is often desirable to first isolate the compound from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back to the free base compound by treating it with an alkaline reagent, followed by converting the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of basic compounds can be readily prepared using conventional techniques, for example, by treating the basic compound with a substantially equivalent amount of a selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Careful evaporation of the solvent yields the desired solid salt. Positively charged compounds (e.g., compounds containing quaternary ammonium) can also form salts with the anionic components of various inorganic and / or organic acids.

[0125] Acids that can be used to prepare pharmaceutically acceptable salts of benglustat are those that can form non-toxic acid addition salts, such as salts with pharmaceutically 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.

[0126] In one embodiment, the pharmaceutically acceptable salt is a succinate salt. In another embodiment, the pharmaceutically acceptable salt is a 2-hydroxysuccinate salt, for example, (S)-2-hydroxysuccinate salt. In another embodiment, the pharmaceutically acceptable salt is a hydrochloride salt (i.e., a salt with HCl). In another embodiment, the pharmaceutically acceptable salt is a malate salt, for example, an L-malate salt.

[0127] The present disclosure also contemplates prodrugs of benglustat. The pharmaceutically acceptable prodrugs disclosed herein are derivatives that can be converted to benglustat in vivo. The prodrugs may have some activity themselves, but become pharmaceutically active in vivo upon, for example, solvolysis under physiological conditions or enzymatic degradation. Methods for preparing prodrugs of benglustat will be apparent to those skilled in the art based on the present disclosure.

[0128] In one embodiment, the carbamate moiety of benglustat is modified. For example, the carbamate moiety can 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 may be considered a hemiacetal or acetal functionality. In one embodiment, the carbamate moiety can be modified by the addition of an aliphatic diol, such as 1,2-ethanediol.

[0129] In one embodiment, the amino group of the quinuclidine moiety is modified. For example, the amino group can be modified to form an acid derivative or a quaternary ammonium salt. Derivatives can be formed, for example, by reacting benglustat with an acetylating agent such as an acid chloride or an alkyl halide.

[0130] The present disclosure further encompasses hydrates, solvates, and polymorphs of benglustat. For example, benglustat may be in one or more crystalline forms, such as those described in International Patent Application No. PCT / US2014 / 027081 (published as WO 2014 / 152215). In one embodiment, benglustat is in the form of crystalline Form A of the malate salt, as described in PCT / US2014 / 027081.

[0131] Isotopically labeled compounds are also within the scope of the present disclosure.As used herein, " isotope-labeled compounds " refers to the compounds of the present disclosure, including pharmaceutical salts and their prodrugs as described herein, wherein one or more atoms are replaced by atoms with atomic mass or mass number different from the atomic mass or mass number that is usually found in nature.The examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Examples include Cl.

[0132] Pharmaceutical Composition In another aspect, the present disclosure provides a pharmaceutical composition (e.g., an oral pharmaceutical dosage form) comprising benglustat in combination with a CYP3A4 inhibitor as defined herein and at least one pharmaceutically acceptable excipient. The composition can be adapted for use in any of the methods disclosed herein.

[0133] The pharmaceutically acceptable excipient can be any such excipient known in the art, including, for example, those described in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985). Pharmaceutical compositions of the compounds of the present disclosure can be prepared by conventional means known in the art, including, for example, mixing at least one compound of the present disclosure with a pharmaceutically acceptable excipient.

[0134] Thus, in embodiments, the present disclosure provides an oral pharmaceutical dosage form comprising benglustat and pharmaceutically acceptable excipients in combination with a CYP3A4 inhibitor (e.g., selected from itraconazole and fluconazole), wherein the dosage form, when orally administered, is formulated to provide a quantity of benglustat sufficient to treat a disease or disorder described according to any of the methods herein.

[0135] In embodiments, benglustat is in a solid crystalline form (e.g., benglustat crystalline malate Form A). In other embodiments, benglustat is in a solid amorphous form. In embodiments, the dosage form comprises an amorphous solid dispersion comprising benglustat and / or a CYP3A4 inhibitor and pharmaceutically acceptable excipients.

[0136] In embodiments, 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 comprising about 2 to about 30 mg of benglustat (measured as the equivalent of the free base), for example, about 4 mg to about 20 mg, or 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 benglustat (measured as the equivalent of the free base).

[0137] In embodiments, the dosage form is a classic tablet or caplet (eg, for swallowing), a chewable tablet, an orally disintegrating tablet, or a dispersible tablet.

[0138] In embodiments, the pharmaceutically acceptable excipients include one or more of: (a) a diluent / filler (e.g., cellulose or microcrystalline cellulose, mannitol, or lactose), (b) a binder (e.g., povidone, methylcellulose, ethylcellulose, hydroxypropylcellulose (such as low-substituted hydroxypropylcellulose), or hydroxypropylmethylcellulose), (c) a disintegrant (e.g., crospovidone, sodium starch glycolate, or croscarmellose sodium), (d) a lubricant (e.g., magnesium stearate or sodium stearyl fumarate), (e) a glidant (e.g., silica or talc), (f) a sweetener (e.g., sucralose, acesulfame potassium, aspartame, saccharin, neotame, or advantame), (g) a flavoring agent (e.g., apricot flavor), and (h) a dye or coloring agent.

[0139] In embodiments, the pharmaceutically acceptable excipient comprises one or more hydrophilic water-soluble or water-swellable polymers, hi embodiments, the polymers are selected from the group consisting of natural or modified cellulosic polymers or any mixture thereof.

[0140] In embodiments, any one or more pharmaceutically acceptable excipients are present in an amount of 0.01 to 80% (by weight), for example, 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%. In an embodiment, the dosage form comprises (a) 5-95% by weight, e.g., 60-70% by weight or 70-80% by weight, or 65-75% by weight, or 65-70% by weight, or about 68% by weight, of a diluent / filler; (b) 0.5-5% by weight, e.g., 1-5% by weight, or 2-4% by weight, or 2-3% by weight, or about 3% by weight, of a lubricant; (c) 2-15% by weight, e.g., 4-12% by weight, or 6-10% by weight, or 7-9% by weight, or about 8% by weight, of a disintegrant. (d) 0-12% by weight, e.g., 2-10% by weight, or 2-8% by weight, or 3-7% by weight, or 4-6% by weight, or about 5% by weight of a binder; (e) 0-5% by weight, e.g., 0.15-4% by weight, or 1-3% by weight, or 1-2% by weight, or about 1% by weight of a lubricant; and (f) 0-2% by weight of a flavoring agent, 0-2% by weight of a sweetener, and / or 0-2% by weight of a coloring agent, e.g., about 1% each of a flavoring agent, a sweetener, and / or a coloring agent. In an embodiment, benglustat is present in an amount of 3%-20% by weight (measured as the free base). In an embodiment, the CYP3A4 inhibitor is present in an amount of 10%-90% by weight.

[0141] In embodiments, the dosage form is a tablet comprising a mixture of benglustat (e.g., benglustat malate), a CYP3A4 inhibitor, and one or more pharmaceutically acceptable excipients. In embodiments, the tablet is formed by direct compression of a mixture of benglustat (e.g., benglustat malate), a CYP3A4 inhibitor, and one or more pharmaceutically acceptable excipients.

[0142] In embodiments, the dosage form is a hard-shell capsule, for example, the capsule contains a mixture of benglustat (e.g., benglustat malate), a CYP3A4 inhibitor, and one or more pharmaceutically acceptable excipients. The benglustat, CYP3A4 inhibitor, and other diluents / carriers may be contained as granules or pellets or a powder, and the granules, pellets, or powder are contained within the capsule shell.

[0143] In embodiments, the benglustat and / or CYP3A4 inhibitor is present in (a) an average particle size of 5-150 μm, e.g., 5-120 μm, 5-100 μm, 10-100 μm, 15-85 μm, 20-60 μm, 30-40 μm, and / or (b) a D90 of 120 μm or less, e.g., 50-100 μm, 70-90 μm, or 60-80 μm, and / or (c) a D10 of 30 μm or less, e.g., 10-25 μm, 10-20 μm or less, or 11-14 μm.

[0144] In embodiments, benglustat and a CYP 3A4 inhibitor are mixed together to form an oral pharmaceutical dosage form, and optionally the dosage form is homogeneous with respect to the distribution of benglustat and the CYP 3A4 inhibitor. In embodiments, benglustat and the CYP 3A4 inhibitor are released over substantially the same period in the gastrointestinal lumen.

[0145] In embodiments, benglustat and the CYP 3A4 inhibitor are contained in separate portions of the composition or dosage form, such as separate compartments, granules, or layers. In embodiments, benglustat and the CYP 3A4 inhibitor are separated by a pharmacologically inert barrier, layer, or shell. In embodiments, benglustat and the CYP 3A4 inhibitor are released over substantially different periods in the gastrointestinal lumen or in different regions of the gastrointestinal lumen (e.g., the mouth, stomach, duodenum, ileum, or jejunum).

[0146] In embodiments, the dosage form is formulated for immediate release of benglustat and / or immediate release of the CYP3A4 inhibitor. In embodiments, the dosage form is formulated for extended release of benglustat and / or extended release of the CYP3A4 inhibitor. In embodiments, the dosage form is formulated for delayed release of benglustat and / or delayed release of the CYP3A4 inhibitor.

[0147] In embodiments, the plasma AUC of benglustat after a single oral dose of 15 mg averages at least 3400 ng-hr / mL, e.g., 3400 to 6200 ng-hr / mL, or 4000 to 5600 ng-hr / mL, or 4400 to 5200 ng-hr / mL.

[0148] Pharmaceutical compositions or dosage forms of the present disclosure may include a drug and another carrier, e.g., a compound or composition, inert or active, e.g., a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffer, salt, lipophilic solvent, preservative, adjuvant, etc. Carriers also include pharmaceutical excipients and additives, such as proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars including monosaccharides, disaccharides, trisaccharides, tetrasaccharides, and oligosaccharides, derivatized sugars such as alditols, aldonic acids, esterified sugars, and polysaccharides or sugar polymers), which may be present alone or in combination and comprise 1 to 99.99% by weight or volume, alone or in combination. Exemplary protein excipients include serum albumins, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, etc. Representative amino acids / antibody components that may also function in a buffering capacity include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, etc. Carbohydrate excipients are also contemplated within the scope of the present disclosure, examples of which include, but are not limited to, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc., disaccharides such as lactose, sucrose, trehalose, cellobiose, etc., polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch, etc., and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), and myo-inositol.

[0149] Carriers that can be used include buffers or pH adjusters, and typically, buffers are salts prepared from organic acids or bases. 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 polymer excipients / additives such as polyvinylpyrrolidone, ficoll (polymeric sugar), dextrates (e.g., cyclodextrins, e.g., 2-hydroxypropyl-β-cyclodextrin), polyethylene glycol, flavoring agents, antibacterial 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).

[0150] The present disclosure also provides pharmaceutical compositions containing benglustat (or a pharmaceutically acceptable salt or prodrug thereof) and a CYP3A4 inhibitor as described herein, as well as kits comprising the compositions. The present disclosure further provides, for example, kits comprising a first pharmaceutical composition comprising benglustat or a pharmaceutically acceptable salt thereof as described herein and a second pharmaceutical composition comprising a strong or moderate CYP3A4 inhibitor as described herein.

[0151] Pharmaceutical compositions can be formulated to provide sustained, extended, or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. Pharmaceutical compositions can also optionally contain opacifying agents and can be compositions that release the active ingredient only or preferentially in a specific portion of the gastrointestinal tract, optionally in a delayed manner, by using, for example, an enteric coating. Examples of encapsulating compositions include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, optionally with one or more pharmaceutically acceptable carriers, excipients, or diluents known in the art (see, e.g., Remington's). The compounds disclosed herein can be formulated for sustained delivery according to methods known to those skilled in the art. Examples of such formulations can be found in U.S. Patent Nos. 3,119,742, 3,492,397, 3,538,214, 4,060,598 and 4,173,626.

[0152] In 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 starch, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, gelatin, pregelatinized maize starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, sucrose, and / or acacia. (3) humectants such as glycerol, (4) disintegrating agents such as agar-agar, calcium carbonate, sodium starch glycolate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (5) solution retardants such as paraffin, (6) absorption accelerators such as quaternary ammonium compounds, (7) wetting agents such as sodium lauryl sulfate, acetyl alcohol, and glycerol monostearate, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, silica, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents. In the case of capsules, tablets, and pills, pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, as well as excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0153] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, and / or dispersants. Molded tablets may be made by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. Tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the art.

[0154] In some embodiments, the pharmaceutical composition is administered orally in liquid form. Liquid dosage forms for oral administration of the active ingredient include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid preparations for oral administration may be provided as a dry product for constitution with water or another suitable vehicle before use. In addition to the active ingredient, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers 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 oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, liquid pharmaceutical compositions can contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, coloring agents, fragrances, and preservatives. Suspensions can contain, in addition to the active ingredient, suspending agents such as, but not limited to, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof. Suitable liquid formulations can be prepared by conventional means using pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methylcellulose, or hydrogenated edible fats), emulsifiers (e.g., lecithin or acacia), non-aqueous vehicles (e.g., almond oil, oily esters, or ethyl alcohol), and / or preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). The active ingredient can also be administered as a bolus, electuary, or paste.

[0155] In some embodiments of the methods described herein, the pharmaceutical compositions may take the form of tablets or lozenges formulated for buccal administration in a conventional manner.

[0156] In some embodiments of the methods described herein, the pharmaceutical composition is administered by parenteral means, such as by topical application, transdermal application, injection, etc. In related embodiments, the pharmaceutical composition is administered parenterally by injection, infusion, or implantation (e.g., intravenously, intramuscularly, intraarterially, subcutaneously, etc.).

[0157] In some embodiments of the methods described herein, the compounds of the present disclosure can be formulated for parenteral administration by injection, including conventional catheterization or infusion. Injectable preparations can be provided in unit dosage form, such as ampoules or multi-dose containers, with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending agents, stabilizing agents, and / or dispersing agents recognized by those skilled in the art. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable vehicle, such as sterile pyrogen-free water, before use.

[0158] In some embodiments of the methods described herein, the pharmaceutical compositions may be in sterile injectable form. Pharmaceutical compositions may be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. To prepare such compositions, the active ingredient is dissolved or suspended in a parenterally acceptable liquid vehicle. Exemplary vehicles and solvents include, but are not limited to, water, water adjusted to an appropriate pH by adding an appropriate amount of hydrochloric acid, sodium hydroxide, or an appropriate buffer, 1,3-butanediol, Ringer's solution, and isotonic sodium chloride solution. Pharmaceutical compositions may also contain one or more preservatives, such as methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, or n-propyl p-hydroxybenzoate. To improve solubility, a solution-enhancing agent or solubilizer may be added, or the solvent may contain 10-60% w / w propylene glycol, etc.

[0159] In some embodiments of the methods described herein, the pharmaceutical compositions may contain one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions immediately before use. Such pharmaceutical compositions may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, suspending agents, thickening agents, preservatives, etc.

[0160] Examples of suitable aqueous and non-aqueous carriers that can be used in any of the pharmaceutical compositions described herein include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.) 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, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. In some embodiments, to prolong the effect of an active ingredient, it is desirable to delay absorption of the compound from gastrointestinal administration or subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the active ingredient depends on its dissolution rate, which may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered active ingredient can be achieved by dissolving or suspending the compound in an oil vehicle. Additionally, prolonged absorption of injectable pharmaceutical forms can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0161] Controlled-release parenteral compositions can be in the form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated into biocompatible carriers, liposomes, nanoparticles, implants, or infusion devices. Materials for use in preparing 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 that can be used when formulating controlled-release parenteral formulations include carbohydrates such as dextran, proteins such as albumin, lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable, such as polydimethylsiloxane, or biodegradable, such as poly(caprolactone), poly(lactic acid), poly(glycolic acid), or poly(orthoesters).

[0162] In some embodiments of the methods described herein, the compounds of the present disclosure can be formulated into ointments or creams for topical administration. The compounds of the present disclosure can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

[0163] In another aspect, the present disclosure provides a dosage form or pharmaceutical composition as described herein for use in treatment, e.g., for use in a method defined herein.

[0164] Having generally described herein, the following non-limiting examples are provided to further illustrate the present disclosure. [Example]

[0165] Example 1A: Synthesis of (S)-quinuclidin-3-yl 2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-ylcarbamate (benglustat) To a stirred solution of 4-fluorothiobenzamide (8.94 g, 57.6 mmol) in ethanol (70 mL) was added ethyl 4-chloroacetoacetate (7.8 mL, 58 mmol). The reaction was heated at reflux for 4 h, treated with an additional aliquot of ethyl 4-chloroacetoacetate (1.0 mL, 7.4 mmol), and refluxed for an additional 3.5 h. The reaction was then concentrated, and the residue was partitioned between ethyl acetate (200 mL) and aqueous NaHCO (200 mL). The organic layer was combined with a back-extract of the aqueous layer (ethyl acetate, 1 × 75 mL), dried (Na SO ), and concentrated. The resulting amber oil was purified by flash chromatography using a hexane / ethyl acetate gradient to afford ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate as a low-melting, nearly colorless solid (13.58 g, 89%).

[0166] To a stirred solution of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate (6.28 g, 23.7 mmol) in DMF (50 mL) was added sodium hydride [60% dispersion in mineral oil] (2.84 g, 71.0 mmol). The foamy mixture was stirred for 15 minutes, then cooled in an ice bath and iodomethane (4.4 mL, 71 mmol) was added. The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then concentrated, and the residue was partitioned between ethyl acetate (80 mL) and water (200 mL). The organic layer was washed with a second portion of water (1 × 200 mL), dried (NaSO), and concentrated. The resulting amber oil was purified by flash chromatography using a hexane / ethyl acetate gradient to give ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate as a colorless oil (4.57 g, 66%).

[0167] To a stirred solution of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoate (4.56 g, 15.5 mmol) in 1:1:1 THF / ethanol / water (45 mL) was added lithium hydroxide monohydrate (2.93 g, 69.8 mmol). The reaction was stirred overnight, concentrated, and redissolved in water (175 mL). The solution was washed with ether (1 × 100 mL), acidified by the addition of 1.0 N HCl (80 mL), and extracted with ethyl acetate (2 × 70 mL). The combined extracts were dried (NaSO) and concentrated to give 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid as a white solid (4.04 g, 98%). This material was used in the next step without purification.

[0168] To a stirred and cooled (0 °C) solution of 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropanoic acid (4.02 g, 15.2 mmol) in THF (100 mL) was added trimethylamine (4.2 mL, 30 mmol), followed by isobutyl chloroformate (3.0 mL, 23 mmol). The reaction was stirred cold for an additional 1 h, after which a solution of sodium azide (1.98 g, 30.5 mmol) in water (20 mL) was added. The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then diluted with water (100 mL) and extracted with ethyl acetate (2 × 60 mL). The combined extracts were washed with aqueous NaHCO (1 × 150 mL) and brine (1 × 100 mL), dried (NaSO), and concentrated. After coevaporation with toluene (2 × 50 mL), the resulting white solid was dissolved in toluene (100 mL) and refluxed for 4 hours. (S)-3-quinuclidinol (3.87 g, 30.4 mmol) was then added, and refluxing was continued overnight. The reaction was concentrated, and the residue was partitioned between ethyl acetate (100 mL) and aqueous NaHCO3 (150 mL). The organic layer was washed with water (1 × 150 mL), dried (Na2SO4), and concentrated. The resulting off-white solid was purified by flash chromatography using a chloroform / methanol / ammonia gradient to give the title compound as a white solid (4.34 g, 73%). 1H NMR(400MHz,CDCl3)δ 7.96-7.88(m,2H),7.16-7.04(m,3H),5.55(br s,1H),4.69-4.62(m,1H),3.24-3.11(m,1H),3.00-2.50(m,5H),2.01-1.26(m,11H)ppm. 13 C NMR(400MHz,CDCl3)δ 166.4,165.1,163.8(d,J=250.3Hz),162.9,155.0,130.1(d,J=3.3Hz),128.4(d,J=8.5Hz),115.9(d,J=22.3Hz),112 .5,71.2,55.7,54.2,47.5,46.5,28.0,25.5,24.7,19.6ppm.Purity: 100% UPLCMS (210nm and 254nm); Retention time 0.83 min; (M+1)390.

[0169] Example 1B: Preparation of the free base form of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (benglustat) Step 1: Dimethylation with methyl iodide [ka] A 3N RB flask was equipped with a thermometer, addition funnel, and 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 and added to the flask via a powder funnel, followed by THF (60 mL). Most of the potassium tert-butoxide dissolved, resulting in a cloudy solution. This mixture was cooled to 0–2 °C (internal temperature) in an ice-water bath. In a separate flask, the starting ester (MW 265.3, 18.85 mmol, 5.0 g, 1.0 equiv.) was dissolved in THF (18 mL + 2 mL rinse) and transferred to the addition funnel. This solution was added dropwise to the cooled mixture over 25–30 min, maintaining the internal temperature below 5 °C during the addition. The reaction mixture was cooled to 0–2 °C. In a separate flask, 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 containing the now clear, colorless THF solution of methyl iodide. This solution was carefully added dropwise to the dark brown reaction mixture over 30–40 min, maintaining the internal temperature below 10°C throughout the addition. After the addition was complete, the slightly cloudy mixture was stirred for an additional 1 h, during which time the internal temperature was allowed to decrease to 0–5°C. After stirring at 0–5°C for 1 h, the reaction mixture was quenched by the slow, dropwise addition of 5.0 M aqueous HCl (8 mL) over 5–7 min. The internal temperature was maintained below 20°C during the 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 as much THF as possible was evaporated in vacuo to obtain a two-phase layer of THF / product and water. The two layers were allowed to separate. The THF solution of the product from step 1 was used in the next reaction.

[0170] Step 2: Hydrolysis of ethyl ester with LiOH monohydrate [ka] The crude ester in THF was added to the reaction flask. LiOH·HO (MW 41.96, 75.0 mmol, 3.15 g, 2.2 equiv.) was weighed into a separate 100 mL beaker containing a stir bar. Water (40 mL) was added, and the mixture was stirred until all solids dissolved, resulting in a clear, colorless solution. This aqueous solution was then added to a 250 mL RB flask containing a solution of the ester in tetrahydrofuran (THF). A condenser was attached to the neck of the flask, and a nitrogen inlet was attached to the top of the condenser. The mixture was heated to reflux for 16 h. After 16 h, heating was stopped, and the mixture was allowed to cool to room temperature. The THF was evaporated in vacuo to yield 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 the basic aqueous solution was extracted with TBME (2 × 40 mL) to remove the t-butyl ester. The basic aqueous layer was cooled to 0-10 °C in an ice-water bath and acidified to approximately pH 1 by dropwise addition of concentrated HCl with stirring. TBME (60 mL) was added to the gummy solid in this acidic aqueous solution, and the mixture was shaken and then vigorously stirred to dissolve all of the acid into the TBME layer. The two layers were transferred to a separatory funnel, and the TBME layer was separated. The pale yellow acidic aqueous 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. The combined TBME layers were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo to remove TBME, yielding the crude acid as an orange / dark yellow oil that solidified under high vacuum to a dirty yellow solid. The crude acid was weighed and crystallized by heating in heptane / TBME (3:1, 5 mL / g crude product) to yield the acid as a yellow solid.

[0171] Step 3: Formation of hydroxamic acids with NH2OH·HCl [ka] 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. THF (5.0 mL) was added, and the acid readily dissolved, yielding a clear, dark yellow to brown solution. The solution was cooled to 0-2 °C (bath temperature) in an ice bath, and N,N'-carbonyldiimidazole (CDI; MW 162.15, 20.74 mmol, 3.36 g, 1.1 equiv.) was added slowly in small portions over 10-15 min. The ice bath was removed, and the solution was stirred at room temperature for 1 h. After stirring for 1 h, the solution was cooled again to 0-2 °C (bath temperature) in an ice-water bath. Hydroxylamine hydrochloride (NH2OH·HCl; MW 69.49, 37.7 mmol, 2.62 g, 2.0 equiv.) was added slowly as a solid in small portions over 3–5 min due to the exothermic nature of the addition. After the addition was complete, water (1.0 mL) was added dropwise to the heterogeneous mixture over 2 min, and the reaction mixture was stirred for 5 min at 0–10 °C in an ice-water bath. The cooling bath was removed, and the reaction mixture was stirred overnight at room temperature under nitrogen for 20–22 h. Once all of the NH2OH·HCl had dissolved, the solution became clear. After 20–22 h, an aliquot of the reaction mixture was analyzed by high-pressure liquid chromatography (HPLC). The THF was then evaporated in vacuo, and the residue was dissolved in dichloromethane (120 mL) and water (60 mL). The mixture was transferred to a separatory funnel, where it was shaken to separate the two layers. The aqueous layer was discarded, and the dichloromethane layer was washed with 1 N hydrochloride (HCl; 60 mL). The acid layer was discarded. The dichloromethane layer was dried over anhydrous Na2SO4, filtered, and the solvent was evaporated in vacuo to give the crude hydroxamic acid as a pale yellow solid, which was dried under high vacuum overnight.

[0172] Step 3 continued: Conversion of the hydroxamic acid to a cyclic intermediate (not isolated) [ka] The crude hydroxamic acid (MW 280.32, 5.1 g) was transferred to a 250 mL 1N RB flask equipped with a nitrogen inlet. A stir bar was added, followed by acetonitrile (50 mL). The solid was insoluble in acetonitrile. The yellow heterogeneous mixture was stirred under nitrogen for 2-3 min, and CDI (MW 162.15, 20.74 mmol, 3.36 g, 1.1 equiv.) was added in one portion at room temperature. No exotherm was observed. The solid dissolved immediately, and the clear yellow solution was stirred at room temperature for 2-2.5 h. After 2-2.5 h, an aliquot was analyzed by HPLC and LC / MS, indicating conversion of the hydroxamic acid to the desired cyclic intermediate.

[0173] The acetonitrile was then evaporated in vacuo to give the crude cyclic intermediate as a thick reddish oil, which was dissolved in toluene (60 mL) and the reddish mixture was heated to reflux for 2 h, during which time the cyclic intermediate released CO and rearranged to the isocyanate (see below). [ka]

[0174] Step 3 continued: Conversion of isocyanate to free base [ka] 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 one portion. The mixture was reheated to reflux for 18 h. After 18 h, an aliquot was analyzed by HPLC and LC / MS, which indicated 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 × 40 mL), and the aqueous layer was separated. The combined aqueous layers were re-extracted with toluene (30 mL), and the aqueous layer was discarded. The combined toluene layers were extracted with 1 N HCl (2 × 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 dropwise addition of 50% w / w aqueous NaOH. The desired free base precipitated from solution as a dirty yellow, gummy solid that could trap the stir bar. Isopropyl acetate (100 mL) was added to the mixture, and the mixture was stirred vigorously for 5 minutes, at which point the gummy solid became isopropyl acetate. Stirring was stopped, and the two layers were allowed to separate. The yellow isopropyl acetate layer was separated, and the basic aqueous layer was re-extracted with isopropyl acetate (30 mL). The basic aqueous layer was discarded, and the combined isopropyl acetate layers were dried over anhydrous Na2SO4 and filtered into a pre-weighed RB flask. The solvent was evaporated in vacuo to give the crude free base as a beige to tan solid, which was dried under high vacuum overnight.

[0175] Step 3 continued: Recrystallization of the crude free base The beige to tan crude free base was weighed and recrystallized 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 with a stir bar, and the mixture was heated to reflux for 10 minutes. (The free base was initially partially soluble, but upon heating to reflux, it dissolved to give a clear, reddish-orange solution.) The heat source was removed, and the mixture was allowed to cool to room temperature with stirring, resulting in the formation of a white precipitate. After stirring at room temperature for 3-4 hours, the precipitate was filtered off under hose vacuum using a Buchner funnel, washed with heptane (20 mL), and dried overnight on the Buchner funnel under hose vacuum. The precipitate was transferred to a crystallizing dish and dried overnight in a vacuum oven at 55°C. 1 H NMR(400MHz,CDCl3)δ 8.04-7.83(m,2H),7.20-6.99(m,3H),5.53(s,1H),4.73-4.55(m,1H),3.18(dd,J=14.5,8.4Hz,1H),3.05-2.19(m,5H),2.0-1.76(m,11H)ppm. 13 C NMR(100MHz,CDCl3)δ 166.38,165.02,162.54,162.8-155.0(d,CF),130.06,128.43,128.34,116.01,11 5.79,112.46,71.18,55.70,54.13,47.42,46.52,27.94,25.41,24.67,19.58ppm.

[0176] Example 2: Preparation of crystalline form of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (benglustat) salt The crystalline salt of (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate can be formed from the free base prepared as described in Example 1B.

[0177] For example, (S)-quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate free base (approximately 50 mmol) is dissolved in IPA (140 mL) at room temperature and filtered. The filtrate is added to a 1 L round-bottom flask equipped with an overhead stirrer and nitrogen inlet / outlet. L-Malic acid (approximately 50 mmol) is dissolved in IPA (100 mL + 30 mL) at room temperature and filtered. The filtrate is added to the 1 L flask. The resulting solution is stirred under nitrogen at room temperature (with or without seeding) for 4 to 24 hours. Crystals form during this period. The product is collected by filtration and washed with a small amount of IPA (30 mL). The crystalline solid is dried in a vacuum oven at 55 °C for 72 hours to yield the desired malate salt.

[0178] Crystalline forms of other salts (eg, acid addition salts with succinic acid or HCl) can be prepared in a similar manner.

[0179] Example 3: Clinical trial of benglustat in healthy volunteers Several Phase 1 studies were conducted in healthy volunteers to determine the pharmacokinetics, pharmacodynamics, safety, and tolerability of benglustat and to evaluate the effect of food on the pharmacokinetics. The studies evaluated single-dose and food effect (clinical trial reference number NCT01674036) and multiple-dose (clinical trial reference number NCT01710826) of benglustat L-malate.

[0180] Study NCT01674036 was divided into two parts. The first part (referred to herein as TDU12766) was a double-blind, randomized, placebo-controlled, sequential ascending-dose study. The second part (referred to herein as FED12767) was an open-label, randomized, two-sequence, two-period, two-treatment crossover study with a minimal washout period to obtain preliminary information on the pharmacokinetics, tolerability, and safety of benglustat after single oral administration in the fed and fasted states. Study NCT01710826 was a double-blind, randomized, placebo-controlled study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of ascending 14-day repeat oral doses of benglustat in healthy male and female subjects (referred to herein as TDR12768).

[0181] Details of the study design, drugs, assessments, measured parameters, and results are described in detail in Peterschmitt et al. (Clin. Pharmacol. Drug Dev. (2021) 10(1):86-98) and in the corresponding clinicaltrials.gov entries for the two studies. Some conclusions are summarized below.

[0182] Venglustat pharmacokinetics after a single dose In a single ascending dose study (TDU12766), across the single oral doses of benglustat malate evaluated (2 to 150 mg), benglustat demonstrated a median t max with a geometric mean t of 28.9 hours 1 / 2 On day 14, mean CL / F ranged from 5.18 to 6.43 L / h across treatment groups. Exposure increased approximately proportionally with dose across the dose range: a 75-fold dose increase resulted in a geometric mean C max , AUC last and AUC infThese studies resulted in a 97.3-fold, 89.2-fold, and 85.9-fold increase in urinary excretion, respectively. The mean 48-hour urinary excretion rates ranged from 14.7% to 23.5% across the 2 to 150 mg dose range. A total of four mild treatment-emergent adverse events (TEAEs) were reported in the 50 to 150 mg dose groups in this study. No adverse events were reported in the 2 to 25 mg dose groups.

[0183] Food Effects In a preliminary evaluation of the food effect on benglustat pharmacokinetics, administration of 5 mg of benglustat malate with a high-fat meal did not affect benglustat exposure compared to fasted conditions. The geometric mean ratio of fed / fasted was C max and AUC last The values ​​were 0.92 and 0.91 for t and t, respectively. Within-subject variability (i.e., fed vs. fasted) accounted for less than half of the total variability within subjects. max The median TEAE was 6.00 hours whether fed or fasted. One subject reported a mild TEAE during the fed phase of the study.

[0184] Venglustat Pharmacokinetics After Multiple Doses In a multiple ascending dose study (TDR12768) in subjects receiving benglustat malate at 5, 10, or 20 mg once daily for 14 days, benglustat was absorbed and the t max The median C was 2.00-5.00 hours. Steady state appeared to be reached within 5 days of repeated dosing. Bengglustat exposure increased dose-proportionally over the dose range of 5-20 mg benglustat malate: this 4-fold dose increase resulted in a geometric mean C of 0.01 on day 14. max and AUC 0-24 After 14 days of administration, the pooled benglustat accumulation ratios were 3.76-fold and 3.69-fold increases in C, respectively, regardless of dose and sex. max is 2.10 and the AUC 0-24 The dose and sex were t 1 / 2 The point estimate of within-subject variability was C max About 14%, AUC0-24 After 14 once-daily doses of benglustat malate, the 24-hour unchanged urinary excretion rate (mean fe 0-24 ) ranged from 26.3% to 33.1%. R(0~24) The plasma CL / F ranged from 1.49 to 2.07 L / h, approximately 3.18 to 3.86-fold lower than the observed plasma CL / F. The geometric mean plasma day 14 / day 1 ratio of 4β-hydroxycholesterol did not show significant differences between the placebo and benglustat-treated groups, indicating minimal induction of CYP3A4. Seventeen 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 benglustat malate group, TEAEs reported by investigators as related to the study drug included constipation, diarrhea, dry mouth, flatulence, pruritus, and fatigue.

[0185] conclusion Following a single oral dose of benglustat malate, benglustat exhibited linear pharmacokinetics, rapid absorption (t max median, 3.00-5.50 h), systemic exposure unaffected by food, low apparent systemic clearance (mean CL / F, 5.18-6.43 L / h), and a pooled geometric mean t of 28.9 h 1 / 2z After 14 days of repeated oral dosing once daily, an apparent steady state occurred within 5 days of repeated dosing, with a pooled accumulation ratio of C max About 2.10, AUC 0-24 The mean RR of 1.28 was 2.22 for 100 mg / kg / day, with no statistically significant effect of dose or gender on accumulation. At the doses and administration regimens tested, benglustat demonstrated a favorable safety and tolerability profile, with no serious adverse events (SAEs) or deaths. There were several TEAEs in the single-dose and multiple-dose groups.

[0186] Example 4: Clinical Trial of Benglestat Co-Administered with Itraconazole Study design A phase I, single-center, open-label, two-period, single-sequence, non-randomized, drug-drug interaction (DDI) study was conducted to evaluate the effect of multiple doses of itraconazole 100 mg BID on the pharmacokinetics of a single dose of benglustat in healthy male subjects under fed conditions with a 7-day washout period between treatment periods. Treatment period 1 (TP1) was 1 day in duration, and treatment period 2 (TP2) was 13 days in duration (see Figure 1).

[0187] Eight subjects enrolled and completed the study. Subjects were men aged 20-43 years with a mean age of 28.8 years. Bengglest (malate form) was administered to subjects on Day 1 of TP1 as hard capsules containing 15 mg of benglustat (equivalent to approximately 20 mg of benglustat malate when measured as the free base). Blood samples were collected pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose on Day 1. Samples were processed to obtain plasma, and benglustat plasma concentrations were determined by HPLC-tandem MS with a lower limit of 0.5 ng / mL. Subjects then underwent a 7-day washout period.

[0188] At the end of the washout period, TP2 began. Subjects received itraconazole twice daily (immediately after breakfast and dinner) from days 1 through 12 of TP2 as commercially available capsules containing 100 mg of itraconazole. On day 6 of TP2, subjects were co-administered benglustat malate as hard capsules containing 15 mg of benglustat (measured as the free base) in addition to the itraconazole dose. Blood samples were collected pre-dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, 72, 96, 120, 144, and 168 hours post-dose on day 6, pre-dose on days 8 and 10, and 12 hours post-dose on day 12. All samples were processed to obtain plasma, and plasma concentrations of benglustat free base were determined in all samples on day 6 by HPLC-tandem MS with a lower limit of quantitation of 0.5 ng / mL. Samples from pre-dose through 12 hours post-dose on day 6 and samples from days 8, 10 and 13 were also analyzed for itraconazole and hydroxyitraconazole concentrations by HPLC-tandem MS at lower limit of 1 ng / mL and 2 ng / mL, respectively.

[0189] The primary endpoint of the study was to evaluate the effect of multiple doses of itraconazole (100 mg BID) on the pharmacokinetics of a single dose of benglustat (15 mg measured as the free base). Secondary endpoints were to evaluate the safety and tolerability of single doses of benglustat with or without co-administration of multiple doses of itraconazole and to evaluate the pharmacokinetics of itraconazole / hydroxyitraconazole.

[0190] Subjects will also be monitored for adverse events (reported by the subject or observed by the investigator), and physical and clinical laboratory evaluations will be performed (hematology, biochemistry, urinalysis). Subjects' temperature, weight, vital signs (heart rate, supine and standing systolic blood pressure, diastolic blood pressure) and a 12-lead electrocardiogram will also be recorded.

[0191] result Overall, benglustat and itraconazole were well tolerated by all subjects. No serious adverse events, adverse events of particular 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 were not considered related to benglustat. The infrequent bowel movements were treated with a daily dose of 5.5 oz of prune juice for 5 days. One subject reported a maculopapular rash on day 6 of TP2, approximately 3 hours after coadministration of benglustat and itraconazole. This rash is listed as a common adverse event in the FDA label for itraconazole and was treated with 50 mg of diphenhydramine (an antihistamine) daily for 6 days.

[0192] Figure 2 shows the mean plasma concentrations of benglustat in the presence and absence of itraconazole. The pharmacokinetic results are summarized in Table 1 below.

[0193] [Table 3]

[0194] These results demonstrate that repeated oral doses of 100 mg BID itraconazole, a strong CYP3A4 inhibitor, and a single dose of 15 mg benglustat significantly improved benglustat AUC last The C of benglustat was demonstrated to increase the C and AUC by 1.79-fold (90% CI: 1.61-1.99) and 2.03-fold (90% CI: 1.81-2.27), respectively, confirming that benglustat is a CYP3A4 substrate in vivo. max increases by 1.12 times, and t 1 / 2z There was a 1.88-fold increase in urinary tract infection (URI) and urinary tract infection (UR). Bengglustat and itraconazole were well tolerated when administered alone or coadministered.

[0195] Example 5: Development and validation of a PBPK model for benglustat plasma concentrations The objectives of this study were to develop and validate a PBPK model using available in vitro and in vivo PK information and to use the PBPK model to predict the PK of benglustat alone or co-administered with a CYP3A inhibitor in healthy subjects to support dosing recommendations.

[0196] A benglustat PBPK model was developed based on in vitro / in vivo absorption, distribution, metabolism, and excretion (ADME) data in healthy subjects and PK data from a Phase 1 clinical trial (Example 3). The Simcyp default "Sim-Healthy Volunteers" population was used to generate the virtual population. PBPK model performance was confirmed using observed benglustat single-dose and multiple-dose PK data from a Phase 1 study in healthy adult subjects. The simulated drug-drug interaction results were validated using the results of an in vivo drug interaction study conducted with itraconazole, a known potent CYP3A4 inhibitor (Example 4), to evaluate the impact of CYP3A inhibition on benglustat exposure.

[0197] Validation of the PBPK model was performed by comparing the predicted and observed plasma concentration-time profiles of benglustat over 14 days with those of healthy subjects after single oral doses of 11.2 mg, 18.6 mg, and 112 mg of benglustat and QD oral doses of 3.72 mg, 7.44 mg, and 14.9 mg of benglustat. The simulated DDI results were validated using a clinical drug interaction study with itraconazole, a known potent CYP3A4 inhibitor (Example 4), to evaluate the contribution of CYP3A4-mediated metabolism in the elimination of benglustat after a single oral dose of 15 mg (measured as the free base). The study design (dose, dosing regimen, age range, and number of virtual subjects) was replicated as closely as possible to ensure that the characteristics of the virtual subjects were consistent with those described in the clinical trial report.

[0198] Software Tools, Model Development and Input Parameters PBPK model development and simulation were performed in Simcyp® Population Based Simulator V17 (Simcyp Ltd, part of Certara, Sheffield, UK) running on Windows Server 2012 R2 Standard with Excel 2013.

[0199] The physicochemical properties of benglustat and its absorption, distribution, metabolism and excretion (ADME) parameters were used as PBPK model inputs and their sources are summarized in Table 2.

[0200] [Table 4]

[0201] [Table 5]

[0202] Consistent with results from previous clinical studies, food intake did not affect benglustat PK. Therefore, primary absorption parameters (e.g., f) of benglustat under fed conditions were evaluated. a , K. a ) was kept the same as that used in the fasted state. The drug distribution of benglustat was reflected by a minimal PBPK model with a single adjustable compartment, which considered both hepatic and intestinal metabolism and lumped other tissues together. The effect of transporters on benglustat PK was assumed to be minimal.

[0203] Model performance was confirmed by predicting observed benglustat exposure ratios of 0.93 to 1.2 after single or repeated oral administration and 1.1 to 1.3 when benglustat was administered alone or coadministered with itraconazole. Benglustat exposures after coadministration 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, respectively, compared to benglustat alone (see Example 5).

[0204] For oral administration, first-order absorption was assumed in all simulations. The fraction absorbed (f a ) and first-order absorption rate constant (K a ) is an estimate of the in vivo permeability, P eff,man and extrapolated from Caco-2 data using standard assays. g ) is Q gut predicted by the model, which represents the nominal blood flow, is a hybrid parameter that reflects the rate of drug absorption from the intestinal lumen, the clearance of drug from enterocytes by the enterocyte blood supply, and the volume of enterocytes. In the absence of information on active drug uptake into enterocytes, f u,gut was set to a default value of 1 (assuming there is insufficient time for plasma protein binding equilibrium or erythrocyte uptake before the drug is cleared from the basolateral side of the enterocyte). uG,int ) calculation was based on the assumption that the intrinsic clearance per pmol of CYP is the same in both the intestine and the liver.

[0205] The unbound fraction in plasma (f u,p ), blood-to-plasma ratio (B / P) and mean percent unbound to human liver microsomal protein (f u,mic ) was measured for benglustat using standard assays. Clinical data from the completed Phase 1 study were initially modeled using population pharmacokinetic (POPPK) methods to derive PK parameters for PBPK model inputs (e.g., distribution parameters, Vss and SAC). Partial metabolism by CYP3A4 and CYP2D6 (f m ) was based on in vitro intrinsic metabolic clearance data. To recover in vivo clearance in PBPK simulations, f from a preliminary POPPK model was used. m Based on the CI and oral clearance (CL / F), the CYP3A4- and CYP2D6-mediated intrinsic clearance was calculated using the Simcyp® built-in reversal calculator. Based on previous studies, the contribution of the renal component to in vivo clearance was estimated to be approximately 30%. The IC of benglustat for human MDR1-mediated transport 50 Values ​​were determined in-house using standard assays.

[0206] Clinical PK data for model validation Concentration-time data of benglustat from the Phase 1 single ascending dose and multiple ascending dose clinical trials (Example 3) were used for benglustat model validation in healthy subjects. The benglustat PBPK model was further validated for PK prediction in the absence and presence of itraconazole, a potent CYP3A inhibitor, in healthy subjects using available data from a clinical DDI study (Example 4). A summary of the clinical trial design of the study used for benglustat PBPK model validation is shown in Table 3.

[0207] [Table 6]

[0208] Validation of the itraconazole and its primary metabolite PBPK models was performed using their PK data from the study in Example 4.

[0209] Simulations were performed using 10 virtual trials for each dose and dosing regimen. Simcyp® uses Monte Carlo methods to simulate the variability of the "Sim-Healthy Volunteers" population. Inter-individual physiological variations (height, weight, age, lymphatic flow, etc.) and, if present, phenotypic variations were automatically calculated using the database in the library. For this analysis, the "PK Profile" option was selected. Therefore, all calculations (dynamic modeling) were time- and concentration-dependent. The overlay-observation option was used to enable validation of the PBPK model based on comparison of the concentration-time profiles between observed and predicted values. To derive PK parameters (e.g., AUC), simulations were performed for at least three half-lives of benglustat in healthy subjects for groups receiving a single dose. For groups receiving multiple doses, simulations were performed until the end of the dosing interval of the last dose, for example, as described in the clinical trials disclosed herein.

[0210] Validation of the benglustat PBPK model in healthy subjects consisted of: A. Graphical comparison of mean (5th and 95th percentile) predicted plasma concentrations (benglustat) and individual observed plasma concentrations from Phase 1 studies (Examples 3 and 4). B. Benggulustat exposure observed in clinical trials (C max , AUC [single dose], AUC 0-24h The observed and predicted PK parameters with corresponding mean ratios (predicted / observed) were also calculated. These ratios should be within a two-fold interval [0.5-2]. C. The performance of the Simcyp® V17 built-in model for the CYP3A inhibitor itraconazole (SVItraconazole_Fed Capsule) and its primary metabolite (SV-OH-itraconazole) was validated by comparing the predicted model and observed data from a clinical study in healthy subjects (Example 4). The PBPK model performance for predicting benglustat-itraconazole interactions was validated using the following methods: A visual prediction test comparing model-predicted means and 90% prediction intervals of plasma concentration-time profiles for benglustat, itraconazole, and OH-itraconazole against individual observed data. Comparison of PK parameters predicted by PBPK with the corresponding mean ratios (predicted / observed) and observed data for itraconazole and OH-itraconazole (steady-state C max , C trough , AUC 0-12h ), Benglestat PK (C) with corresponding geometric mean ratios (predicted values ​​divided by observed values) max ratio, AUC last Observed and predicted drug interaction ratios (AUC ratio and AUC ratio) were also calculated. The predicted vs. observed values ​​should be within a two-fold interval [0.5 to 2].

[0211] The final PBPK model was used to predict the effect of CYP3A4 inhibitors on the steady-state PK of benglustat in healthy subjects. Each simulation consisted of 10 virtual trials in 10 subjects aged 18 to 65 years with a 50 / 50 male / female ratio coadministered with the inhibitor, following repeated administration of benglustat to reach steady state. The library virtual population "Sim-Healthy Volunteers" was used for model application. The study design varied depending on the inhibitor characteristics and the anticipated clinical scenario. Simulations were run for a time sufficient to reach steady-state PK of benglustat and the CYP3A inhibitor in healthy subjects when coadministered.

[0212] Two scenarios were evaluated to predict DDIs between benglustat inhibitors and CYP3A inhibitors: first, assuming that the subject is already receiving benglustat treatment and requires concomitant CYP3A inhibitor therapy; and second, assuming that the subject is already receiving CYP3A inhibitor medication before starting benglustat treatment. The simulation study design for each of these scenarios for each performer is described as follows: For inhibitors, the maximum dose and dosage regimen most commonly used in clinical practice or the maximum approved dose was generally selected to maximize the likelihood of DDIs.

[0213] Each virtual subject received multiple oral doses of 15 mg QD or 8 mg QD starting on day 1. In healthy subjects, repeated doses of 100 mg BID itraconazole were co-administered with benglustat from days 6 to 17.

[0214] To simulate benglustat exposure when coadministered with a strong CYP3A inhibitor (e.g., itraconazole), the following clinical scenarios were assumed: Each virtual subject received multiple oral doses of benglustat 15 mg QD on days 1 through 5, then switched to 8 mg QD on days 6 through 17. In healthy subjects, repeated doses of 100 mg BID itraconazole were co-administered with benglustat on days 6 through 17.

[0215] Each virtual subject received multiple oral doses of 100 mg BID itraconazole starting on day 1. Repeat doses of 15 mg QD or 8 mg QD benglustat were co-administered with itraconazole starting on day 10 until steady state was achieved with benglustat.

[0216] As a final step, the above model was compared with a similar model built using an updated version of Simcyp® (V19) with an updated library model for SV-Itraconazole_fed Capsule. In V19, in addition to the first-order absorption model as the default itraconazole cmpz file, users can select the Advanced Dissolution, Absorption, and Metabolism (ADAM) option to reflect factors affecting the rate and extent of oral drug absorption. Based on the above evaluation, it was concluded that the itraconazole compound library file used in V17 adequately describes itraconazole PK. Compared to V17, the majority of model parameters remain the same in the V19 itraconazole cmpz library file. The predicted V ss The slight difference in V is likely due to the updated system parameter values ​​and the addition of inhibition parameters for multiple transporters expressed in the intestine and liver. To further understand the impact of the V19 update on the prediction results, partial validation of both itraconazole models (first-order absorption and ADAM models) was performed using the data from Example 4. The simulation settings were identical to those shown above.

[0217] C max , AUC last The predicted benglustat PK parameters of the V19 model, including AUC and drug interaction ratio, were similar to those obtained using the V17 model. However, the prediction accuracy of the V19 itraconazole model with ADMA absorption was unacceptable and therefore was not used for further modeling.

[0218] Results - Single and Repeated QD Administration of Venglustat The observed and predicted benglustat concentrations in healthy male subjects after single oral doses of 11.2 mg, 18.6 mg, and 112 mg (calculated as the free base) of benglustat using the PBPK model are shown in Figures 3 and 4. The benglustat PK parameters observed in clinical trials were compared with those predicted by the PBPK model, and the results are shown in Table 4 below.

[0219] [Table 7]

[0220] The observed and predicted benglustat concentrations in healthy male and female subjects after repeated QD administration of 3.72 mg, 7.44 mg, and 14.9 mg of benglustat using the PBPK model are shown in Figures 5 and 6. The benglustat PK parameters observed in clinical trials were compared to those predicted by the PBPK model in Table 5 below.

[0221] [Table 8]

[0222] As demonstrated by the graphical comparisons shown in Figures 3-6, the majority of individual observed concentration-time points were within the 5th and 95th percentiles of the predicted plasma concentrations. The PBPK model was able to adequately predict benglustat exposure in healthy subjects on Day 1 after a single dose and on Day 14 after repeated QD administration of benglustat. The differences between the observed and predicted mean PK parameters were within 20%, and the mean predicted / observed ratios were within the range of 0.93 to 1.2, which was within the specified 2-fold interval.

[0223] Results – Single dose of benglustat in the absence and presence of itraconazole Simulated plasma concentration-time profiles of benglustat on day 6 after a single 15 mg dose calculated as the free base, in the absence and presence of 100 mg itraconazole co-administration BID from days 1 through 12, are shown in Figures 7 and 8, respectively. Benglustat (15 mg single dose) was administered alone during treatment period 1 (as in Example 4). The observed and simulated PK profiles are shown in Figures 7A and 8A, respectively, over a limited time window of 120 to 288 hours. Virtual healthy male subjects were generated and randomly assigned to 10 different trials of 8 subjects each to demonstrate inter-group variability. For each simulation, concentration-time profiles representative of the total virtual population (n=80) are shown. The predicted mean C max , AUC last and AUC ratios are shown in Table 6 below.

[0224] [Table 9]

[0225] The simulated concentration-time profiles of itraconazole and its primary metabolite (hydroxyitraconazole) with overlaid observations are shown in Figures 9 and 10, respectively. The PK parameters of itraconazole and hydroxyitraconazole observed in the clinical trial (Example 4) were compared with those predicted by the PBPK model in Table 7 below.

[0226] [Table 10]

[0227] As demonstrated by the graphical comparisons shown in Figures 7-10, nearly all of the observed individual concentration-time points were within the 5th and 95th percentiles of the predicted plasma concentrations. The PBPK model was able to adequately predict benglustat exposure in healthy male subjects, with or without itraconazole co-administration. The geometric mean ratios of the observed and predicted treatment ratios (C max ratio, AUC lastThe AUC ratio and AUC ratio were approximately 0.9. Therefore, model performance was considered acceptable. Furthermore, the PBPK model accurately captured the PK profiles of itraconazole and hydroxyitraconazole on day 6 after repeated BID administration in healthy subjects, with the observed and predicted differences within two-fold. Collectively, the collected evidence confirmed the validity of the PBPK model for predicting benglustat DDIs with CYP3A inhibitors, including itraconazole.

[0228] Example 6: Application of a PBPK model to predict steady-state plasma concentrations of benglustat co-administered with a CYP3A inhibitor The validated PBPK model of Example 5 was used to predict benglustat PK at repeat doses of 8 and 15 mg in healthy subjects co-administered with other CYP3A inhibitors to guide dose recommendations.

[0229] method Simulations of the pharmacokinetics (PK) of benglustat were performed in 10 virtual trials in 10 subjects aged 18-65 years, co-administered with a CYP3A inhibitor, with a 50 / 50 male / female ratio, after repeated doses of benglustat to reach steady state. The virtual population was generated using Simcyp®'s built-in "Sim-Healthy Volunteers." The pharmacokinetics (PK) of benglustat (C) relative to the last dose was max , AUC tau , C max Ratio and AUC tau The predicted PK parameters and DDI ratios of the 200 mg / kg / day (DDI ratio) were calculated.

[0230] Prediction of steady-state plasma concentrations of benglustat after repeated oral administration was performed in healthy subjects using (i) fluconazole, a moderate CYP3A4 inhibitor; (ii) fluvoxamine, a moderate CYP3A4 inhibitor; and (iii) cimetidine, a weak CYP3A inhibitor. CYP2D6 inhibition was turned off in this model.

[0231] The Simcyp® V17 library model for fluconazole (SV-fluconazole), a moderate CYP3A inhibitor, was used for model application without modification. The model input parameters for fluvoxamine (a moderate CYP3A inhibitor) and cimetidine (a weak CYP3A inhibitor) in the simulation had the default values ​​shown in the compound library file (SV-fluvoxamine and SV-cimetidine, respectively) in the Simcyp simulator (V17), except for a minor modification: turning off the inhibitory effect on CYP2D6, since both CYP3A and CYP2D6 inhibition were incorporated into the library model. This allowed the effects of fluvoxamine and cimetidine on benglustat to be evaluated solely through the CYP3A pathway.

[0232] The fluconazole PBPK model was further validated using clinical data from the literature describing the effect of fluconazole on midazolam exposure (Olkkola et al., Anesth. Analg. (1996) 82(3):511-516). The predicted C values ​​of midazolam in healthy subjects after a single oral dose of 7.5 mg midazolam on days 1 and 6 in the absence and presence of fluconazole were max and AUC ratios are shown below in Table 8. To compare the observed AUC ratios obtained from the reported AUC from time 0 to infinity, two independent simulations were performed to generate corresponding ratios for midazolam on days 1 and 6.

[0233] [Table 11]

[0234] The ratio between predicted and observed PK parameters was approximately 1. The results showed good quality of the model for DDI prediction with fluconazole as a moderate CYP3A inhibitor.

[0235] These modified PBPK models were tested for the effects of fluvoxamine / cimetidine on sensitive CYP3A substrates based on published clinical data studying the effects of fluvoxamine on a sensitive CYP3A substrate (midazolam) and the effects of cimetidine on several sensitive CYP3A substrates (midazolam, nifedipine, and sildenafil) (see, e.g., Lam et al., J. Clin. Pharmacol. (2003) 43(11):1274-1282; Fee et al., Clin. Pharmacol. Ther. (1987) 41(1):80-84; Schwartz et al., Clin. Pharmacol. Ther. (1988) 43(6):673-80; and Wilner et al., Br. J. Clin. Pharmacol. (2002) 53(Suppl 1):31S-36S). Predicted mean C in healthy subjects after single oral doses of midazolam / nifedipine / sildenafil in the absence and presence of CYP3A inhibitors max and AUC ratios are shown in Table 9 below.

[0236] [Table 12]

[0237] The PBPK model was able to adequately predict the DDI potential of fluvoxamine and cimetidine in healthy subjects. The ratios between predicted and observed PK parameters were approximately 1. Taken together, the results confirmed the good quality of the DDI prediction model using fluvoxamine and cimetidine as moderate and weak CYP3A inhibitors, respectively.

[0238] Effect of coadministration with other CYP3A4 inhibitors on benglustat exposure Plasma PK parameters of benglustat 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 (ages 18-65 years; female, 50%) were generated and randomly assigned to 10 different trials of 10 subjects to demonstrate inter-group variability. The predicted mean C of benglustat at steady state in the presence and absence of the corresponding inhibitors was max and AUC tau Ratios were also generated.

[0239] [Table 13]

[0240] conclusion This analysis enabled the development of a PBPK model for benglustat in healthy adults based on available physicochemical and in vitro / in vivo absorption, distribution, metabolism, and excretion (ADME) data. The model was fully validated using information from single-dose and multiple-ascending-dose clinical studies of benglustat (Example 3) and a clinical DDI study using itraconazole as a potent CYP3A inhibitor (Example 4). The predicted plasma concentration profiles (benglustat, itraconazole, and hydroxyitraconazole) were consistent with the data observed in clinical trials. Nearly all observed individual concentrations fell within the predicted 90% confidence intervals, and the predicted-to-observed ratios for PK parameters were within two-fold. Drug interaction ratios were also well captured, further confirming the contribution of CYP3A4-mediated metabolism to the overall clearance of benglustat in healthy subjects. Therefore, the benglustat model developed and validated using Simcyp V17 could be used to predict the PK of benglustat when coadministered with other CYP3A inhibitors.

[0241] In April 2020, Simcyp Ltd. released Simcyp® Population Based Simulator V19 with an updated library model for SV-Itraconazole_Fed Capsule. Based on the above evaluation, it was decided to utilize the itraconazole PBPK model V17 for the final simulation. The SV-fluconazole library model was used without modification, and further validation using available clinical data demonstrated its good performance for model application. The modified Simcyp library model for fluvoxamine / cimetidine was validated for its effects on sensitive CYP3A substrates based on published clinical data as described above, and model performance was deemed acceptable for model application.

[0242] In summary, a benglustat PBPK model was developed using Simcyp V17. The model was validated for PK prediction in the absence and presence of a strong CYP3A inhibitor (itraconazole) in healthy adult subjects. Co-administration of benglustat with a CYP3A inhibitor is predicted to result in higher exposure, with the magnitude of the effect depending in part on the potency of the inhibitor. Bengglustat steady-state AUC after co-administration with strong and moderate CYP3A inhibitors tau was predicted to be 1.69-fold higher for itraconazole, 1.52-fold higher for fluconazole, and 1.08-fold higher for fluvoxamine. The effect of the weak CYP3A inhibitor cimetidine on benglustat systemic exposure was thought to be minimal (1.08-fold higher).

[0243] These results indicate that coadministration of some (but not all) CYP3A4 inhibitors may require dose adjustment of benglustat to maximize the safety and efficacy of treatment. The results observed in the models between different inhibitors also suggest that the effect of any given inhibitor on benglustat exposure is not easily predictable, such that selecting appropriate dose adjustments may not be straightforward without guidance from the PBPK model developed herein.

[0244] While the present disclosure has been described in conjunction with the above embodiments, it should be understood that the foregoing descriptions and examples are intended to illustrate, but not limit, the scope of the present disclosure. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains.

[0245] Additionally, those skilled in the art will recognize that when a feature or aspect is described in terms of a Markush group, such feature or aspect is also described in terms of any individual member or subgroup of members of the Markush group.

[0246] All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety to the same extent as if each were individually incorporated by reference. In the case of conflict, the present specification, including definitions, will control.

Claims

1. A method for treating a disease or disorder in a subject in need thereof, comprising administering an effective amount of benglustat or a pharmaceutically acceptable salt thereof to the subject, wherein the subject is concurrently receiving a strong or moderate inhibitor of CYP3A4.

2. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of benglustat or a pharmaceutically acceptable salt thereof, wherein the subject is concurrently administered an inhibitor of CYP3A4, whereby the plasma exposure (e.g., AUC) of benglustat is increased by about 5% to 25% compared to the exposure resulting from administration of benglustat in the same dosage, form and regimen in the absence of the CYP3A4 inhibitor.

3. 3. The method of claim 2, wherein the benglustat or the pharmaceutically acceptable salt thereof is administered at a dosage of about 12 mg / day or about 15 mg / day (calculated as the free base).

4. 2. The method of claim 1, wherein the CYP3A4 inhibitor is a potent inhibitor that increases the plasma exposure of benglustat by about 60% to 120% compared to the exposure resulting from administration of benglustat at the same dose, form and regimen in the absence of the CYP3A4 inhibitor, and wherein the benglustat or a pharmaceutically acceptable salt thereof is administered at a dosage of about 4 mg to 15 mg per day (calculated as the free base).

5. 5. The method of claim 4, wherein the benglustat or the pharmaceutically acceptable salt thereof is administered at a dosage of about 8 mg / day (calculated as the free base).

6. 2. The method of claim 1, wherein the CYP3A4 inhibitor is a moderate inhibitor that increases the plasma exposure of benglustat by about 40% to 60% compared to the exposure resulting from administration of benglustat at the same dose, form and regimen in the absence of the CYP3A4 inhibitor, and wherein the benglustat or the pharmaceutically acceptable salt thereof is administered at a dosage of about 12 mg to 15 mg per day (calculated as the free base).

7. 7. The method of claim 6, wherein the benglustat or the pharmaceutically acceptable salt thereof is administered at a dosage of about 15 mg / day (calculated as the free base).

8. 8. The method of any one of claims 1 to 7, wherein the benglustat is in the form of benglustat free base, a pharmaceutically acceptable salt of benglustat or a prodrug of benglustat, optionally benglustat L-malate.

9. The method according to any one of claims 1 to 8, wherein the benglustat or the pharmaceutically acceptable salt thereof and the CYP3A4 inhibitor are administered in combination, for example in the same pharmaceutical composition.

10. 10. The method according to any one of claims 1 to 9, wherein the benglustat or the pharmaceutically acceptable salt thereof is administered orally, and the CYP3A4 inhibitor is administered transmucosally, intravenously, or orally.

11. 11. The method of any one of claims 1 to 10, wherein the disease or disorder is selected from lysosomal storage diseases (e.g., Gaucher disease or Fabry disease), proteinopathies (e.g., Alzheimer's disease, Parkinson's disease or Huntington's disease), cystic diseases (e.g., polycystic kidney disease) and ciliopathy (e.g., Bardet-Biedl syndrome).

12. 12. The method of any one of claims 1 to 11, wherein the subject has a comorbidity selected from a fungal infection, a viral infection, a bacterial infection, a mood disorder, and cancer.

13. 13. Benglustat or a pharmaceutically acceptable salt thereof (or a combination of benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor, such as a composition comprising benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor) for use in the method according to any one of claims 1 to 12.

14. 13. Use of benglustat or a pharmaceutically acceptable salt thereof (or a combination of benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor, such as a composition comprising benglustat or a pharmaceutically acceptable salt thereof and a CYP3A4 inhibitor) in the manufacture of a medicament for use in a method according to any one of claims 1 to 12.

15. A method for optimizing (e.g., reducing) the dosage of benglustat in a subject being treated or intended to be treated with benglustat or a pharmaceutically acceptable salt thereof, the method comprising administering to the subject a strong or moderate CYP3A4 inhibitor.

16. 1. A method of minimizing drug-drug interactions between benglustat and a moderate or strong CYP3A4 inhibitor in a subject suffering from a disease or disorder amenable to treatment with benglustat or a pharmaceutically acceptable salt thereof, the method comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in combination with said CYP3A4 inhibitor, compared to the exposure that would result from administration of benglustat in the same dosage, form, and regimen in the absence of said CYP3A4 inhibitor; and (ii) adjusting the dosage of said benglustat or said pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

17. A method for establishing the correct dosage of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in combination with a strong or moderate CYP3A4 inhibitor, compared to the exposure resulting from administration of benglustat in the same dosage, form and regimen in the absence of the CYP3A4 inhibitor; and (ii) reducing the dosage of benglustat or a pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

18. A method for improving the dosing regimen of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising: (i) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor, compared to the exposure resulting from administration of benglustat in the same dosage, form and regimen in the absence of the CYP3A4 inhibitor; and (ii) reducing the dosage of benglustat or a pharmaceutically acceptable salt thereof if the change in plasma exposure is an increase of more than about 25%.

19. 1. A method of managing the risk of benglustat / CYP3A4 inhibitor interaction in a subject having a disease or disorder amenable to treatment with benglustat or a pharmaceutically acceptable salt thereof, comprising: (i) initiating treatment in said subject with benglustat or a pharmaceutically acceptable salt thereof at a standard prescribed dose; (ii) determining the change in plasma exposure of benglustat when benglustat or a pharmaceutically acceptable salt thereof is administered in conjunction with a strong or moderate CYP3A4 inhibitor compared to said exposure resulting from administration of benglustat in the same dosage, form and regimen in the absence of said CYP3A4 inhibitor; and (iii) reducing the dosage if said change in plasma exposure is an increase of more than about 25%.

20. Use of a strong or moderate CYP3A4 inhibitor in a method for (a) establishing the correct dosage of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, (b) improving the dosing regimen of benglustat or a pharmaceutically acceptable salt thereof in a subject in need thereof, or (c) managing the risk of benglustat / CYP3A4 inhibitor interaction in a subject having a disease or disorder amenable to treatment with benglustat or a pharmaceutically acceptable salt thereof, wherein the subject is receiving or is intended to be receiving the CYP3A4 inhibitor.

21. A method for inhibiting CYP3A4 activity in a subject being treated with benglustat or a pharmaceutically acceptable salt thereof, comprising administering said benglustat or said pharmaceutically acceptable salt thereof simultaneously with a strong or moderate CYP3A4 inhibitor.

22. A method for improving the therapeutic response to benglustat treatment in a subject in need thereof, comprising administering benglustat or a pharmaceutically acceptable salt thereof concomitantly with a strong or moderate CYP3A4 inhibitor.

23. A pharmaceutical composition (e.g., an oral pharmaceutical dosage form) comprising benglustat or a pharmaceutically acceptable salt thereof in combination with a strong or moderate CYP3A4 inhibitor and at least one pharmaceutically acceptable excipient.

24. 24. The composition of claim 23, formulated for oral administration.

25. 25. The composition of claim 24, in 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).

26. A composition according to any one of claims 23 to 25 for use in a method according to any one of claims 1 to 22.

Images