Venglustat as an inhibitor of glucosylceramide synthase in subjects having hepatic impairment

Abstract

Provided herein are methods in which subjects having hepatic impairment are administered venglustat. The methods are directed, in particular, at subjects having mild or moderate hepatic impairment.

Description

[0001] VENGLUSTAT AS AN INHIBITOR OF GLUCOSYLCERAMIDE SYNTHASE IN SUBJECTS HAVING HEPATIC IMPAIRMENT

[0002] Provided herein are methods in which subjects having hepatic impairment are administered venglustat. The methods typically involve administering the same amount of venglustat which would be administered to a subject having normal hepatic function, although the methods may involve making specific adjustments to the venglustat dosage in order to optimise the clinical response of the subject.

[0003] BACKGROUND

[0004] Venglustat (also known as (5)-quinuclidin-3-yl 2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2- ylcarbamate) is a small molecule drug which has been 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 hereby incorporated by reference in their entirety. It has been suggested that venglustat, which is an inhibitor of the enzyme glucosylceramide synthase (GCS), might act in these treatments by: reducing glycolipid levels (e.g., in the case of lysosomal storage diseases); reducing protein aggregation (e.g., in the case of proteinopathies); decreasing apoptosis (e.g., in the case of cystic diseases); or improving the function of ciliary bodies in ciliated epithelial cells (e.g., in the case of ciliopathies).

[0005] Small molecule GCS inhibitors, such as venglustat, are primarily intended for oral administration on a regular (e.g., daily) basis. Compounds administered orally may be subject to first-pass metabolic deactivation by the liver, which can reduce their oral bioavailability. Thus, oral dosage forms can sometimes require larger dosages to achieve therapeutic efficacy than would be required if the active agent were administered via another route (e.g., intravenously). This, in turn, can increase the risks when administering to subjects having hepatic impairment, who may require a lower dose, for example in order to improve safety measures.

[0006] In the case of venglustat, both hepatic and renal routes have been implicated in clearance of the drug / / / vivo. In particular, the hepatic enzyme cytochrome P45o 3A4 (CYP3A4) has been implicated in the metabolic pathway of venglustat, although the clinical significance of P450 involvement has not been established (See, e.g., Peterschmitt etal., Clin. Pharmacol. Drug Dev. (2021) 10(l):86-98).

[0007] To date, clinical studies using venglustat as an active agent have excluded participants who have a history of, or who currently suffer from, hepatic disease (See, e.g., Peterschmitt et cd.. 2021, supra). There is, therefore, a need to develop treatments in which venglustat can be administered safely and effectively to subjects having hepatic impairment.

[0008] SUMMARY

[0009] The present disclosure describes clinical studies which have been carried out to assess the impact of hepatic impairment on venglustat exposure in vivo. These studies have enabled the development of venglustat dosage regimens and treatment methods which are safe and effective for the treatment of subjects having hepatic impairment.

[0010] Thus, the present disclosure provides the following aspects and embodiments (items El to E25):

[0011] El . A method for treating a disease or disorder in a subject having impaired hepatic function, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

[0012] E2. The method of El, wherein the impaired hepatic function is mild, moderate, or severe hepatic impairment.

[0013] E3. The method of El orE2, wherein the impaired hepatic function is of class A, B, or C according to the Child-Pugh Score.

[0014] E4. A method for treating a disease or disorder in a subject having mild or moderate hepatic impairment, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

[0015] E5. The method of E4, wherein the hepatic impairment is of class A or B according to the Child-Pugh Score. E6. The method of E4 or E5, wherein the venglustat or pharmaceutically acceptable salt thereof is administered at a dose that would be administered to a subject having the same disease or disorder but not having impaired hepatic function.

[0016] E7. The method of any one of E4 to E6, wherein the venglustat or pharmaceutically acceptable salt thereof is administered at a dosage of 15 mg per day (calculated as the free base).

[0017] E8. A method for treating a disease or disorder in a subject having severe hepatic impairment, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

[0018] E9. The method of E8, wherein the venglustat or pharmaceutically acceptable salt thereof is administered at a dosage of 6 mg per day (calculated as the free base).

[0019] El 0. The method of any one of El to E9, wherein 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., autosomal dominant polycystic kidney disease (ADPKD), or autosomal recessive polycystic kidney disease (ARPKD)), and a ciliopathy (e.g., Bardet-Biedl syndrome).

[0020] El 1. The method of El 0, wherein the disease or disorder is a lysosomal storage disease.

[0021] El 2. The method of El 1, wherein the method further comprises administering to the subject an effective amount of a lysosomal enzyme.

[0022] E13. The method of El 1 or El 2, wherein the disease or disorder is Gaucher disease (e.g., Gaucher disease type 3), optionally wherein the lysosomal enzyme is glucocerebrosidase.

[0023] El 4. The method of El 1 or El 2, wherein the disease or disorder is Fabry disease, optionally wherein the lysosomal enzyme is alpha-galactosidase.

[0024] El 5. The method of any one of El to El 4, wherein the subject is not concurrently being administered a CYP3 A inhibitor (e.g. a strong CYP3 A4 inhibitor).

[0025] El 6. Venglustat or a pharmaceutically acceptable salt thereof, for use in a method according to any one of El to El 5. E17. Venglustat or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a subject having impaired hepatic function.

[0026] El 8. Venglustat or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a subject having mild or moderate hepatic impairment.

[0027] E19. Venglustat or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject having severe hepatic impairment.

[0028] E20. A method of providing venglustat, or a pharmaceutically acceptable salt thereof, wherein the venglustat, or pharmaceutically acceptable salt thereof, is provided along with information that it is useful for treating subjects having hepatic impairment and that no dose adjustment is required in subjects having mild or moderate hepatic impairment.

[0029] E21 . The method of E20, wherein in accordance with the information the method comprises selecting a dose of venglustat, or pharmaceutically acceptable salt thereof, to be administered which is the same as the dose that would be administered to a subject not having hepatic impairment.

[0030] E22. A package comprising venglustat, or a pharmaceutically acceptable salt thereof, and a label, wherein the label comprises a statement that venglustat, or a pharmaceutically acceptable salt thereof, is indicated for the treatment of subjects having mild or moderate hepatic impairment.

[0031] E23. The package of E22, wherein the label comprises a statement that the venglustat or pharmaceutically acceptable salt thereof should be administered as a once daily dose of 15 mg (measured as the free base).

[0032] E24. The package of E22 or E23, wherein the label comprises a statement that there is no effect of mild or moderate hepatic impairment on venglustat exposure, and / or that there is no clinically relevant change in venglustat exposure in subjects having mild or moderate hepatic impairment, and / or that no dose adjustment is required in subjects having mild or moderate hepatic impairment.

[0033] E25. The package of any one of E22 to E24, wherein the label comprises a statement that there is limited data on exposure of venglustat or a pharmaceutically acceptable salt thereof in subjects having severe hepatic impairment, and / or that venglustat or a pharmaceutically acceptable salt thereof may be administered to subjects with severe hepatic impairment with caution.

[0034] Additional features and advantages of the compositions and methods disclosed herein will be apparent from the following detailed description.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Fig- 1 shows the graphical study design for a clinical trial to assess pharmacokinetic response to orally administered venglustat in subjects with mild, moderate, and severe hepatic impairment (Example 3).

[0037] Fig- 2 shows the mean (+SD) plasma concentration-time profiles for venglustat (GZ402671) following a single oral administration of venglustat in participants with normal hepatic function (N=8), and mild (N=8), moderate (N=8), and severe (N=2) hepatic impairment (linear scale).

[0038] Fig- 3 shows the mean (+SD) plasma concentration-time profiles for venglustat (GZ402671) following a single oral administration of venglustat in participants with normal hepatic function (N=8), and mild (N=8), moderate (N=8), and severe (N=2) hepatic impairment (semi-logarithmic scale).

[0039] DETAILED DESCRIPTION

[0040] Although specific embodiments of the present disclosure will now be described with reference to the preparations and schemes, it should be understood that such embodiments are by way of example only and merely illustrative of but a small number of the many possible specific embodiments which can represent applications of the principles of the present disclosure. Various changes and modifications will be obvious to those of skill in the art given the benefit of the present disclosure and are deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0041] Definitions

[0042] Unless defined otherwise, all technical and scientific terms used herein have the same meanings 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 the present disclosure, exemplary methods, devices, and materials are now described. All technical and patent publications cited herein are incorporated herein by reference in their entirety. The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of organic synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art. All numerical designations, e.g., pH, temperature, time, concentration, molecular weight, etc., including ranges, are approximations which are varied ( + ) or ( - ) by increments of, e.g., 0.1 or 1 .0, where appropriate. It is to be understood, although not always explicitly stated, that all numerical designations are preceded by the term “about”, which is used to denote a conventional level of variability. For example, a numerical designation which is “about” a given value may vary by ± 10% of said value; alternatively, the variation may be ± 5%, ± 2%, or ± 1% of the value. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely exemplary and that equivalents of such are known in the art.

[0043] As used in the specification and claims, the singular form “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise. For example, the term “an inhibitor” includes a plurality of inhibitors, including mixtures thereof. Unless specifically stated or obvious from context, as used herein, the term “or” is understood to be inclusive. The term “including” is used herein to mean, and is used interchangeably with, the phrase “including but not limited to”.

[0044] As used herein, the term “comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but do not exclude others. “Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate buffered saline, preservatives, and the like. “Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure or process steps to produce a composition or achieve an intended result. Embodiments defined by each of these transition terms are within the scope of this disclosure. Use of the term “comprising” herein is intended to encompass both “consisting essentially of’ and “consisting of’. A “subject”, “individual”, or “patient” is used herein to refer to a human. The terms “subject”, “individual”, and “patient” are generally used interchangeably herein, but the skilled reader will appreciate from the context when a subject or individual is a healthy individual. The term “healthy individual” as used herein typically denotes an individual who does not have hepatic impairment, e.g. an individual having normal hepatic function. A “healthy individual” also typically does not have renal impairment, e.g. does not suffer from renal disease. Thus, a healthy individual typically does not have a history or presence of: alcohol or recreational drug abuse, hepatic disease (e.g., hepatitis), renal disease (e.g., polycystic kidney disease), obesity, hemochromatosis, cirrhosis, jaundice, liver cancer, kidney cancer, or genetic risk factors associated with liver or kidney disease. In embodiments, a healthy individual does not suffer from a condition which is amenable to treatment with venglustat. For example, a healthy individual may be an individual who does not suffer from a lysosomal storage disease such as Gaucher disease, a proteinopathy such as Alzheimer’s disease or Parkinson’s disease, a cystic disease such as polycystic kidney disease, or a ciliopathy such as Bardet-Biedl Syndrome. A healthy individual typically does not have any mutations in the GBA gene (encoding glucocerebrosidase). Indeed, a healthy individual may lack mutations in any gene which encodes an enzyme involved in the glycosphingolipid pathway, for example mutations in the genes encoding ceramide synthase, glucosylceramide synthase, galactosylceramide synthase, lactosylceramide synthase, sphingomyelin synthase, ceramidase, glucocerebrosidase, saposin, galactosylceramide P- galactosidase, acid sphingomyelinase, arylsulphatase A, agalactosidase A, P-hexosaminidase (e.g., Hex A or Hex B), sialidase, GMl-P-galactosidase, GM2 ganglioside activator protein, glucosyl transferase, and galactosyl transferase.

[0045] “Administering” is defined herein as a means of providing an agent (e.g., active ingredient) or a composition containing the agentto a subject in a manner that results in the agent being inside the subject’s body, including prescribing, instructing, managing, or supervising the subject or another in providing the agent or composition to the subject. Such an administration can be by any route including, without limitation, oral, dermal, transdermal, transmucosal (e.g., vaginal, rectal, buccal, or sublingual), by injection (e.g., subcutaneous, intravenous, intraperitoneal, intrathecal, intramuscular, intradermal), and by inhalation (e.g., pulmonary, intranasal). Pharmaceutical preparations are, of course, given by forms suitable for each administration route. Administration may also be local or systemic in nature. For example, while oral and injectable routes of administration generally provide systemic exposure, some routes of administration only provide 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 directed towards enteral, e.g. oral, administration.

[0046] As used herein, “concurrent” and “concurrently” when referring to a therapeutic use means administration of two or more active ingredients to a patient as part of a regimen for the treatment of a disease or disorder, whether the two or more active agents are given at the same or different times or whether given by the same or different routes of administrations. The terms “concomitant” and “in conjunction with” as used herein are intended to have an equivalent meaning. Concurrent administration of the two or more active ingredients may be at different times on the same day, or on different dates or at different frequencies.

[0047] Concurrent administration of the two or more active agents may be intended to treat a single disease or disorder in the patient, but it is typically used herein to refer to the administration of two or more active agents which are effective in treating two or more different diseases or disorders, e.g., wherein each active agent is effective in treating a separate disease or disorder independently of the other active agent(s).

[0048] “Treating” or “treatment” of a disease includes: (1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease; (2) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and / or (3) relieving the disease, i.e. causing regression of the disease or its clinical symptoms. A disease which is “amenable to treatment” with or “treatable by” a particular active agent is a disease which can be treated and / or prevented by the active agent in at least some patients who are suffering from the disease or who are predisposed to the disease.

[0049] The term “suffering” as it relates to the term “treatment” refers to a patient or individual who has been diagnosed with the disease. The term “suffering” as it relates to the term “prevention” refers to a patient or individual who is predisposed to the disease. A patient may also be referred to being “at risk of suffering” from a disease because of a history of disease in their family lineage or because of the presence of genetic mutations associated with the disease. A patient at risk of a disease has not yet developed all or some of the characteristic pathologies of the disease. An “effective amount” or “therapeutically effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, and the route of administration. It is understood, however, that specific dose levels of the therapeutic agents of the present disclosure for any particular subject depend upon a variety of factors including, for example, the activity of the specific compound employed, the age, body weight, general health, sex, and diet of the subject, the time of administration, the severity of the particular disorder being treated, and the form of administration. Typically, dosage-effect relationships fromzn vitro and / or in vivo tests initially can provide useful guidance on suitable doses for patient administration. In general, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro.

[0050] Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to treat (e.g., improve) one or more symptoms associated with a disease or disorder described herein, ex vivo, in vitro, or in vivo. A “standard indicated dose” refers to the recommended amount of a therapeutic agent for a subject in the absence of variables which may require dose adjustment, e.g., concurrent administration with one or more additional agents as defined herein or subjects suffering from other conditions which might impact dosing of the active agent. Where such variables are present, an “adjusted dose” or “adjusted effective amount” may be administered - this may be the same amount or a different amount of the therapeutic agent as compared with a “standard indicated dose” or an “effective amount” for a different (e.g., an average) subject.

[0051] As used herein, “CYP” is an abbreviation for Cytochrome P450 (or Cytochrome Oxidase P450), a family of mammalian enzymes expressed predominantly in the liver which are largely responsible for the oxidative metabolism of many drugs. There are at least 57 common types of CYP enzymes, and these are grouped into families. The CYP3 A family includes, among other enzymes, CYP3 A4. CYP3 A4 is the predominant cytochrome involved in the metabolism of venglustat and it is responsible for about 80% of venglustat metabolism in human liver microsomes. As used herein, the term “inhibitor” has its commonly recognized pharmacological meaning. An inhibitor is thus a compound (typically a small molecule) which inhibits, either competitively or non-competitively (e.g., allosterically) the functioning of an enzyme, receptor, or other macromolecular target (e.g., protein). Inhibitors generally operate either by binding to the active site of an enzyme or receptor, blocking access by the normal substrate, or by binding to an allosteric site which results in a conformational change in the enzyme or receptor which reduces the enzyme or receptor’s activity. Competitive inhibitors bind to the active site, and may cause either reversible or irreversible inhibition, the latter often by covalent attachment to the active site. Inhibition of an enzyme in the presence of a compound may also occur indirectly, e.g., if one or more metabolites of the compound are themselves inhibitors (e.g., reversible or irreversible, and / or competitive or non-competitive inhibitors) of the enzyme.

[0052] As used herein, the term “CYP3 A4 inhibitor” therefore refers to a small molecule compound which inhibits the enzymatic activity of the CYP3 A4 enzyme, either competitively or non- competitively, and either reversibly or irreversibly. CYP3 A4 inhibitors can be described as strong, moderate, or weak (See, e.g.: “Common Medications Classified as Weak, Moderate and Strong Inhibitors of CYP3A4”, EBM Consult (October 2015), which can be accessed at https: / / www.ebmconsuk.com / articles / medications-inhibitors-cyp3a4-enzyme; and Flockhart “Drug Interactions: Cytochrome P450 Drug Interaction Table”, Indiana University School of Medicine (2007), which can be accessed at http s: / / drug-in / ier action s.medi gin e. iu.edu). Examples of strong CYP3 A4 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, wild cherry, echinacea angiislifolia. fluvoxamine, aprepitant, ciprofloxacin, crizotinib, cyclosporine, dronedarone, imatinib, isavuconazole, and tofisopam. Examples of weak CYP3A4 inhibitors include cimetidine, chlorzoxazone, cilostazol, clotrimazole, fosaprepitant, istradefylline, ivacaftor, lomitapide, ranitidine, ranolazine, and ticagrelor.

[0053] As used herein, the term “inducer” has its commonly recognized pharmacological meaning. An inducer is thus a compound (typically a small molecule) which increases the functioning of an enzyme, receptor, or other macromolecular target (e.g., protein). As used herein, the term “CYP3 A4 inducer” therefore refers to a small molecule compound which induces the amount and / or enzymatic activity of the CYP3 A4 enzyme, Examples of strong CYP3 A4 inducers are describedin, e.g., Flockhart (supra) and include carbamazepine, enzalutamide, and rifampin.

[0054] As used herein, the term “pharmaceutically acceptable excipient” encompasses any of the standard pharmaceutical excipients, including carriers such as a phosphate buffered saline solution, water, and emulsions, such as an oil / water orwater / oil emulsion, and various types of wetting agents. Pharmaceutical compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see Remington’s Pharmaceutical Sciences (20thed., Mack Publishing Co. 2000).

[0055] As used herein, the term “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.

[0056] Addition salts can be readily prepared using conventional techniques, e.g., by treating a base compound with a defined amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol.

[0057] Compounds that are positively charged, e.g., containing a quaternary ammonium, may also form salts with the anionic component of various inorganic and / or organic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts are those which can form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate [i.e., 1,1 ’- methylene-bis-(2 -hydroxy-3 -naphthoate)] salts. Bases which can be used to prepare the pharmaceutically acceptable base addition salts are those which can form non-toxic base addition salts, e.g., salts containing pharmacologically acceptable cations, such as, alkali metal cations (e.g., potassium and sodium), alkaline earth metal cations (e.g., calcium and magnesium), ammonium or other water-soluble amine addition salts such as N- methylglucamine (meglumine), lower alkanolammonium, and other such bases of organic amines. Addition salts of venglustat are typically acid addition salts. In embodiments, the pharmaceutically acceptable salt of venglustat is venglustat malate, in particular venglustat L- m al ate.

[0058] A mass quantity of venglustat referred to herein corresponds, unless explicitly stated otherwise, to a mass of venglustat calculated as free base. For example, a “15 mg dose of venglustat” refers to an amount of 15 mg of venglustat free base, or to an amount of a salt or prodrug of venglustat which provides an equivalent molar quantity (e.g., 20 mg of venglustat malate salt). Accordingly, references to “venglustat” throughout this specification include the pharmaceutically acceptable salts and prodrugs of venglustat, e.g. as described herein.

[0059] The recitation of an embodiment for a variable or aspect herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0060] Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.

[0061] The following abbreviations are used herein:

[0062] Ap amyloid-beta

[0063] ADPKD autosomal dominant polycystic kidney disease

[0064] ALT alanine transaminase

[0065] ARPKD autosomal recessive polycystic kidney disease

[0066] AST aspartate aminotransferase

[0067] AUC area under the plasma concentration to time curve

[0068] AUCO-12 12-hour AUC (AUC0.24 = 24-hour AUC)

[0069] AUC , area under the plasma concentration to time curve (also AUCinf)

[0070] AUCiast area under the plasma concentration to time curve from zero to hast

[0071] BBS Bardet-Biedl syndrome

[0072] BMI body mass index

[0073] CDI carbonyldiimidazole

[0074] Cmaxmaximum observed plasma concentration

[0075] CI confidence interval

[0076] CL / F apparent total body clearance from plasma

[0077] CP-A Child-Pugh class A

[0078] CP-B Child-Pugh class B

[0079] CP-C Child-Pugh class C cps cycles per second

[0080] CV % coefficient of variance

[0081] CYP cytochrome P450 (or cytochrome oxidase P450)

[0082] DDI drug-drug interaction(s)

[0083] DMF dimethylformamide

[0084] DNA deoxyribonucleic acid

[0085] ECG electrocardiogram

[0086] EDTA ethylenediaminetetraacetic acid eGFR estimated glomerular filtration rate

[0087] EOS end of study

[0088] ERT enzyme replacement therapy

[0089] GBA glucocerebrosidase gene

[0090] GCS glucosylceramide synthase

[0091] GD Gaucher disease

[0092] GM1 monosialotetrahexosylganglioside

[0093] GM2 monosialotrihexosylganglioside

[0094] HCV hepatitis C virus

[0095] Hex P-hexosaminidase

[0096] HI hepatic impairment

[0097] HIV human immunodeficiency virus

[0098] HPC hydroxypropylcellulose

[0099] HPLC high pressure / performance liquid chromatography

[0100] HSA human serum albumin

[0101] IMP investigational medicinal product

[0102] INR international normalized ratio of coagulation

[0103] IPA isopropyl alcohol

[0104] LC / MS liquid chromatography mass spectrometry

[0105] LLOQ lower limit of quantification

[0106] MS mass spectrometry

[0107] PK pharmacokinetics

[0108] PKD polycystic kidney disease

[0109] Q.S. quantum satis - enough to make up the intended amount

[0110] RB round bottomed rHA recombinant human albumin RNA ribonucleic acid

[0111] SAE serious adverse event

[0112] SD single dose ti / 2 half-life ti / 2zterminal half-life associated with the terminal slope hast time of last dose tmaxtime to peak concentration (Cmax)

[0113] TBME tert-butyl methyl ether

[0114] TE treatment-emergent

[0115] TEAE treatment-emergent adverse event

[0116] THF tetrahydrofuran

[0117] Tris tris(hydroxymethyl)aminomethane

[0118] TWEEN 20 polysorbate 20

[0119] TWEEN 80 polysorbate 80

[0120] Wt. % percentage by weight

[0121] UPLCMS ultra performance liquid chromatography mass spectrometry

[0122] Vssapparent volume of distribution at steady state

[0123] Administration of venglustat to subjects having hepatic impairment

[0124] Venglustat (free base) has a chemical structure according to Formula I below, and it may conveniently be provided in the form of a malate addition salt (e.g., prepared as described in the following Examples).

[0125] Venglustat is an oral GCS inhibitor under development for the treatment of, e.g., Fabry disease and Gaucher disease. Venglustat is cleared by hepatic and renal routes.

[0126] Previous clinical trials using venglustat have excluded participants having impaired hepatic function. There is, therefore, no clinical available information about the level of exposure of venglustat in these patient populations. At the outset of the study, an increase in exposure (AUC) of venglustat was anticipated in participants having hepatic impairment as compared to participants having normal hepatic function. As such, it was postulated that a reduced dosage might be required in subjects having hepatic impairment.

[0127] It has now been determined, however, that hepatic impairment does not significantly increase the plasma exposure of venglustat, and that no dosage adjustment is required to provide a safe and effective treatment. In the clinical study described in the following examples, participants having mild and moderate hepatic impairment showed comparable venglustat exposure to participants with normal hepatic function when administered a standard indicated dosage. As a precaution, participants having severe hepatic impairment were administered a reduced dosage of venglustat in the study, but the dose-normalized exposure which was observed was below the average exposure observed in individuals having normal hepatic function. The small number of participants having severe hepatic function in the study, however, meant that a detailed analysis of the impact of venglustat in that population was not feasible.

[0128] Hepatic impairment can be assessed, e.g., using the Child-Pugh classification. The criteria for a Child-Pugh scoring are known to the skilled person and are described, e.g., in Example 3 below. Based on the total Child-Pugh score, subjects can for example be classified as having: mild hepatic impairment (HI) if they have a total score of from 5 to 6 (Child-Pugh class A); moderate HI if they have a total score of from 7 to 9 (Child-Pugh class B); and severe HI if they have a total score of 10 or more (Child-Pugh class C). In embodiments, the hepatic impairment of the subject assessed and / or treated in accordance with the present disclosure is determined using the Child-Pugh classification, e.g. as described herein.

[0129] Alternatively, hepatic impairment can be determined by assessing the disease type and / or severity of specific conditions in the subject, for example the type and / or severity of hepatitis (e.g., viral, alcoholic, or autoimmune hepatitis), hepatic steatosis, non-alcoholic fatty liver disease, hemochromatosis, Wilson’s disease, alpha 1 -antitrypsin deficiency, glycogen storage disease type II, amyloidosis, cirrhosis, and primary or secondary liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, or hemangiosarcoma of the liver). The assessment of the presence or severity of hepatic impairment may comprise the determination of elevated ALT and / or AST levels in the subject, e.g., long-term measurement of elevated ALT and / or AST levels which may be monitored using conventional methods. In embodiments, the hepatic impairment of the subject assessed and / or treated in accordance with the present disclosure is determined according to the type and severity of their disease and / or the symptoms thereof, e.g. as described above. Thus, the present disclosure provides, for the first time, concrete guidance for the skilled person looking to treat conditions responsive to venglustat with that drug in subjects having hepatic impairment. Viewed from this aspect, the disclosure provides a method for treating a disease or disorder in a subject having impaired hepatic function, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof. In a related aspect, the disclosure provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein the subject has hepatic impairment. In another related aspect, the disclosure provides a method of administering venglustat or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject has hepatic impairment.

[0130] In a related aspect, the disclosure provides venglustat or a pharmaceutically acceptable salt thereof for use in a method of the disclosure, e.g. for use in a method for treating a disease or disorder in a subject having impaired hepatic function, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof. A further related aspect provides the use of venglustat or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method of the disclosure, e.g. for use in a method for treating a disease or disorder in a subject in need thereof, wherein the subject has hepatic impairment.

[0131] In another aspect, the disclosure provides venglustat or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a subject having impaired hepatic function (e.g., in a subject having mild or moderate hepatic impairment, or in a subject having severe hepatic impairment). In another aspect, the disclosure provides the use of venglustat or a pharmaceutically acceptable salt thereof for treating a disease or disorder in a subject having impaired hepatic function (e.g., in a subject having mild or moderate hepatic impairment, or in a subject having severe hepatic impairment).

[0132] In embodiments, the hepatic impairment is mild, moderate, or severe hepatic impairment, e.g as determined by Child-Pugh classification. Mild and moderate hepatic impairment

[0133] In embodiments, the hepatic impairment is mild hepatic impairment or moderate hepatic impairment, e.g. as determined by Child-Pugh classification (e.g. being of class A or B according to the Child-Pugh Score). Viewed from this aspect, the disclosure provides a method for treating a disease or disorder in a subject having mild or moderate hepatic impairment, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof. In a related aspect, the disclosure provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein the subject has mild or moderate hepatic impairment. In another related aspect, the disclosure provides venglustat or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a subject having mild or moderate hepatic impairment. The disclosure further provides the use of venglustat or a pharmaceutically acceptable salt thereof in treating a disease or disorder in a subject having mild or moderate hepatic impairment.

[0134] In embodiments, the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage which is the same as the standard indicated dosage. Thus, in embodiments the hepatic impairment is mild hepatic impairment or moderate hepatic impairment, and the venglustat or pharmaceutically acceptable salt is administered at a dose which is the same as the dose that would be administered to a subject suffering from the same disease or disorder but not having impaired hepatic function. In embodiments, the hepatic impairment is mild hepatic impairment or moderate hepatic impairment and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 15 mg per day (calculated as the free base).

[0135] In embodiments, the hepatic impairment is moderate hepatic impairment, e.g. as determined by Child-Pugh classification (e.g. being of class B according to the Child-Pugh Score). In such embodiments, the venglustat or pharmaceutically acceptable salt thereof may be administered in a dosage which is the same as the standard indicated dosage, e.g. administered in a dosage of about 15 mg per day (calculated as the free base).

[0136] In embodiments, the hepatic impairment is mild hepatic impairment, e.g. as determined by Child-Pugh classification (e.g. being of class A according to the Child-Pugh Score). In such embodiments, the venglustat or pharmaceutically acceptable salt thereof may be administered in a dosage which is the same as the standard indicated dosage, e.g. administered in a dosage of about 15 mg per day (calculated as the free base).

[0137] Severe hepatic impairment

[0138] In embodiments, the hepatic impairment is severe hepatic impairment, e.g. as determined by Child-Pugh classification (e.g. being of class C according to the Child-Pugh Score). Viewed from this aspect, the disclosure provides a method for treating a disease or disorder in a subject having severe hepatic impairment, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof. In a related aspect, the disclosure provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein the subject has severe hepatic impairment. In a related aspect, the disclosure provides venglustat or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a subject having severe hepatic impairment. The disclosure further provides the use of venglustat or a pharmaceutically acceptable salt thereof in treating a disease or disorder in a subject having severe hepatic impairment.

[0139] In embodiments, the hepatic impairment is severe hepatic impairment, and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 6 mg per day (calculated as the free base).

[0140] Disorders

[0141] In the aspects of the disclosure described herein, the disease or disorder is amenable to treatment with venglustat (or a pharmaceutically acceptable salt thereof). In embodiments, the disease or disorder is selected from a lysosomal storage disease, a proteinopathy, a cystic disease, and a ciliopathy.

[0142] In embodiments, the disease or disorder is a lysosomal storage disease selected from Fabry disease, Gaucher disease (e.g., GD type 1, type 2, or type 3), a GM1 -gangliosidosis, a GM2- gangliosidosis (e.g., GM2-activator deficiency, Tay-Sachs disease, Sandhoff disease, or AB Variant), sialidosis, Niemann-Pick disease (e.g., Type C), and Krabbe disease. In embodiments, the disease or disorder is selected from Gaucher disease, andFabry disease. In one embodiment, the disease or disorder is Fabry disease. In another embodiment, the disease or disorder is Gaucher disease. In one embodiment, the disease or disorder is type 3 Gaucher Disease (GD3).

[0143] Where the disease or disorder is a lysosomal storage disease, the method may further comprise administering to the patient an effective amount of a lysosomal enzyme. Administration of a lysosomal enzyme typically seeks to reduce the levels of (i.e., debulk) accumulated substrate in affected tissues. The lysosomal enzyme is selected to supplement (or reintroduce) the enzyme activity which is reduced (or lacking) in the disease in question. Such a treatment is known as enzyme replacement therapy (ERT) and is well established in clinical practice for treating lysosomal storage diseases. Examples of authorized ERTs include treating patients having Gaucher disease with glucocerebrosidase (e.g., imiglucerase - Cerezyme®, from Sanofi) and treating patients having Fabry disease with alphagalactosidase (e.g., agalsidase beta - Fabrazyme®, from Sanofi). Concurrent administration of venglustat with an ERT is thus contemplated in the present disclosure. The ERT may be administered simultaneously, sequentially, or separately to the administration of venglustat. For example, the venglustat may be administered daily (e.g., once daily) and the ERT administered weekly or fortnightly. In embodiments, the disease or disorder is Gaucher disease (e.g., Gaucher disease type 3) and the lysosomal enzyme is glucocerebrosidase. In other embodiments, the disease or disorder is Fabry disease and the lysosomal enzyme is alpha-galactosidase.

[0144] In embodiments, the disease or disorder is a proteinopathy selected from Alzheimer’s disease, Parkinson’s disease, Lewy Body Dementia, Pick’s disease, progressive supranuclear palsy, dementia pugilistica, parkinsonism linked to chromosome 17, Lytico-Bodig disease, tangle predominant dementia, Argyrophilic grain disease, ganglioglioma, gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, corticobasal degeneration, frontotemporal dementia, frontotemporal lobar degeneration, and Huntington’s disease. 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, alpha-synuclein protein aggregates, and / or amyloid-beta (AP) aggregates in the central nervous system. In an embodiment, the disease or disorder is Alzheimer’s disease. In another embodiment, the disease or disorder is Parkinson’s disease. In embodiments, the disease or disorder is a cystic disease selected from polycystic kidney disease, polycystic liver disease, and polycystic ovary disease. In embodiments, the cystic disease is polycystic kidney disease (PKD), e.g., autosomal dominant PKD (ADPKD) or autosomal recessive PKD (ARPKD).

[0145] In embodiments, the disease or disorder is a ciliopathy selected from Joubert syndrome, Meckel-Gruber syndrome, Senior-Loken syndrome, Orofaciodigital syndrome type I, Leber’s congenital amaurosis, Bardet-Biedl syndrome (BBS), Alstrbm syndrome, Jeune asphyxiating thoracic dystrophy, Ellis van Creveld syndrome, Sensenbrenner syndrome, primary ciliary dyskinesia, and combinations thereof. In embodiments, the ciliopathy is BBS.

[0146] Dosages, dosage forms, and modes of administration

[0147] Dosage forms of venglustat for use in accordance with the present disclosure will typically comprise a standard indicated dosage amount of venglustat or a pharmaceutically acceptable salt thereof. The standard indicated dosage may be different, for example, in the case of different medical indications and / or patient types. Thus, for example, a paediatric or juvenile subject may receive a lower standard indicated dosage of venglustat than an adult. Dosages of venglustat or a pharmaceutically acceptable salt thereof for use in accordance with the present disclosure will typically be in the range of about 4 mg per day to about 30 mg per day (measured as the free base). For example, venglustat or a pharmaceutically acceptable salt thereof may be administered in a dosage of from about 8 mg to about 20 mg per day, e.g., from about 12 mg to about 16 mg per day, such as about 15 mg per day (calculated as the free base). In embodiments, the aforementioned dosage, e.g. the dosage of about 15 mg per day, is administered to an adult subject (e.g., aged 18 years or over, who may have a bodyweight of > 50 kg). In embodiments, the subject is a juvenile or adolescent subject (e.g., aged below 18 years, who may have a bodyweight of < 50 kg) and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage from about 4 mg to about 15 mg per day (calculated as the free base). In embodiments, the juvenile or adolescent subject has a body weight of 10 kg to < 15 kg and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 4 mg per day (calculated as the free base), e.g. as a once daily dose of a tablet comprising 4 mg of venglustat (calculated as the free base). In embodiments, the juvenile or adolescent subject has a bodyweight of 15 kgto < 30 kg and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 6 mg per day (calculated as the free base), e.g. as a once daily dose of a tablet comprising 6 mg of venglustat (calculated as the free base). In embodiments, the juvenile or adolescent subject has a body weight of 30 kg to < 50 kg and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 12 mg per day (calculated as the free base), e.g. as a once daily dose of two tablets each comprising 6 mg of venglustat (calculated as the free base). In embodiments, the juvenile or adolescent subject has a bodyweight of > 50 kg and the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage of about 15 mg per day (calculated as the free base), e.g. as a once daily dose of a tablet comprising 15 mg of venglustat (calculated as the free base).

[0148] In embodiments, the venglustat is in the form of venglustat free base, a pharmaceutically acceptable salt of venglustat, or a prodrug of venglustat. In one embodiment, the venglustat is in the form of venglustat malate salt, e.g., venglustat L-malate, optionally in crystalline form. In embodiments, the venglustat is provided in a dosage form comprising an amount of a pharmaceutically acceptable salt of venglustat corresponding to 15 mg of venglustat free base (e.g., about 20 mg, such as 20.16 mg, of venglustat malate).

[0149] In embodiments, the venglustat or pharmaceutically acceptable salt or prodrug thereof is administered transmucosally, intravenously, or orally. In embodiments, the venglustat or pharmaceutically acceptable salt or prodrug thereof is administered orally. In embodiments, the venglustat or pharmaceutically acceptable salt or prodrug thereof is administered without regard to meals (e.g., with or without food).

[0150] In embodiments, the venglustat or pharmaceutically acceptable salt thereof is administered in the form of an oral pharmaceutical composition (e.g., as described herein). 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 embodiments, the tablet or capsule comprises 4 mg, 6 mg, 8 mg, 10 mg, 12 mg, or 15 mg of venglustat (calculated as the free base). In embodiments, the tablet or capsule comprises 4 mg of venglustat (calculated as the free base). In embodiments, the tablet or capsule comprises 6 mg of venglustat (calculated as the free base). In embodiments, the tablet or capsule comprises 15 mg of venglustat (calculated as the free base). In an embodiment, the oral pharmaceutical composition is a formulation as described in international patent application No. PCT / IB2021 / 056673 (published as WO 2022 / 018695), the entire content of which is incorporated by reference herein. In embodiments, the venglustat or pharmaceutically acceptable salt or prodrug thereof is administered once daily, e.g. as a single unit dosage form. In other embodiments, the venglustat or pharmaceutically acceptable salt or prodrug thereof is administered twice daily, e.g. as two separate unit dosage forms.

[0151] In embodiments, the formulation is a tablet having the following composition:

[0152] In embodiments, the tablet contains 15 mg of venglustat (20. 16 mg of venglustat malate) and the weight of the tablet is 150 mg. In other embodiments, the tablet contains 6 mg of venglustat (8.06 mg of venglustat malate) and the weight of the tablet is 60 mg.

[0153] CYP3A inhibitors and inducers

[0154] In embodiments, the subject is not concurrently being administered an inhibitor or an inducer of CYP3 A, e.g. a CYP3 A4 inhibitor. In embodiments, the subject is not concurrently being administered a moderate or strong inhibitor of CYP3A4. In embodiments, the subject is not concurrently being administered a strong inducer of CYP3A4. In embodiments, the subject is not concurrently being administered a moderate or strong inhibitor of CYP3 A4 or a strong inducer of CYP3 A4.

[0155] In embodiments, the strong CYP3A4 inhibitor is selected from clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, troleandomycin, voriconazole, ceritinib, and idelalisib. In embodiments, the moderate CYP3 A4 inhibitor is selected from fluconazole, amiodarone, erythromycin, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, conivaptan, chamomile, licorice, wild cherry, echinacea anguslifolia. fluvoxamine, aprepitant, ciprofloxacin, crizotinib, cyclosporine, dronedarone, imatinib, isavuconazole, and tofisopam. In embodiments, the strong CYP3 A4 inducer is selected from carbamazepine, enzalutamide, and rifampin. Plasma exposure

[0156] The present disclosure provides methods by which venglustat can be dosed such that the plasma exposure of venglustat in subjects having hepatic impairment is comparable to the plasma exposure of individuals who do not have hepatic impairment. Viewed from this aspect, the disclosure provides a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein said subject has hepatic impairment, whereby the plasma exposure (e.g., as characterised by AUC and / or Cmax) of venglustat in said subject is increased by less than about 50% as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual (e.g., an individual suffering from the same disease or condition which is responsive to venglustat but who does not have hepatic impairment). In this way, a standard dosage can be safely administered to the subject having hepatic impairment, and can provide a plasma exposure which is similar to the exposure from a standard dosage in an individual not having hepatic impairment.

[0157] In a related aspect, the disclosure provides venglustat or a pharmaceutically acceptable salt thereof for use in a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein the subject has hepatic impairment, whereby the plasma exposure (e.g., AUC and / or Cmax) of venglustat in said subject is increased by less than about 30% as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual. A further related aspect provides the use of venglustat or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in a method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof, wherein the subject has hepatic impairment, whereby the plasma exposure (e.g., AUC and / or Cmax) of venglustat is increased by less than about 30% as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual. Methods for determining the difference in plasma exposure between healthy individuals and subjects having hepatic impairment are described herein, including in the following examples. In the foregoing aspects of the disclosure, the disease or disorder is amenable to treatment with venglustat (or a pharmaceutically acceptable salt thereof). Exemplary diseases and disorders which are treatable by venglustat are described herein. Standard doses of venglustat are described herein and include, e.g., doses of about 15 mg per day (calculated as the free base).

[0158] In embodiments, the plasma exposure of venglustat is characterised by the AUC of venglustat. In embodiments, the AUC is the AUCo-n, AUC0-24, AUCo- h, AUC^t, or AUC , . In embodiments, the plasma exposure of venglustat is the AUCiast of venglustat. In embodiments, the plasma exposure of venglustat is the AUC , of venglustat. Plasma exposure of venglustat can be measured after a single dose, or at steady state after multiple doses. Typically, the plasma exposure is measured the same way in the healthy individual and in the subject having hepatic impairment, e.g. in the same time interval(s) after a single dose (e.g., a single oral dose) or at a steady state after the same number and type of doses (e.g., once-daily oral doses administered 24 hours apart). In embodiments, the plasma exposure is AUC , measured after a single dose. In other embodiments, the plasma exposure of venglustat is characterised by the Cmaxof venglustat. In embodiments, the plasma exposure of venglustatis the Cmaxof venglustat measured after a single dose. In embodiments, the plasma exposure of venglustat is characterised by the AUC and the Cmax of venglustat measured after a single dose.

[0159] In embodiments, the AUC of venglustat is increasedby less than about 25% as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual. In embodiments, the AUC of venglustat is increased in a subject having hepatic impairment by less than about 20%, 15%, 10%, or 5%, as compared to the exposure resulting from administration of venglustat in the same form and regimen to a healthy individual. In embodiments, a subject having hepatic impairment has an AUC of venglustat which is between about 80% and about 160%, between about 85% and about 150%, or between about 90% and about 140% (such as about 110%, or about 115%, or about 120%) as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual.

[0160] In embodiments, the Cmax of venglustat is increased by less than about 20% (e.g., less than about 15%) as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual. In embodiments, the Cmaxof venglustat is not increased in a subject having hepatic impairment as compared to the exposure resulting from administration of venglustat in the same form and regimen to a healthy individual. In embodiments, a subject having hepatic impairment has a Cmaxof venglustat which is between about 50% and about 120%, between about 60% and about 100%, or between about 70% and about 90% (such as about 75%, or about 80%) as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual.

[0161] In embodiments, the subject has mild or moderate hepatic impairment, e.g. as assessed by Child-Pugh classification as described herein. In embodiments, the subject has mild hepatic impairment, e.g. as assessed by Child-Pugh classification as described herein. In embodiments, the subject has mild hepatic impairment and has an AUC of venglustat which is increased by about 10% (or about 15% or about 20%) and / or a Cmaxof venglustat which is about 80% as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual. In other embodiments, the subject has moderate hepatic impairment, e.g. as assessed by Child-Pugh classification as described herein. In embodiments, the subject has moderate hepatic impairment and has an AUC of venglustat which is increased by about 15% (or about 20% or about 25%) and / or a Cmax of venglustat which is about 70% as compared to the exposure resulting from administration of a standard dose of venglustat in the same form and regimen to a healthy individual.

[0162] Forms of venglustat

[0163] The present disclosure contemplates salt forms of venglustat, e.g., venglustat in the form of a pharmaceutically acceptable salt.

[0164] Compounds that are basic in nature are generally capable of forming a wide variety of different salts with various inorganic and / or organic acids. Although such salts are generally pharmaceutically acceptable for administration to animals and humans, it is often desirable in practice to initially isolate a compound from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds can be readily prepared using conventional techniques, e.g. by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as, for example, methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.

[0165] Compounds that are positively charged, e.g., containing a quaternary ammonium, may also form salts with the anionic component of various inorganic and / or organic acids.

[0166] Acids which can be used to prepare pharmaceutically acceptable salts of venglustat are those which can form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate [i.e., l,l ’-methylene-bis-(2 -hydroxy-3 -naphthoate)] salts.

[0167] In one embodiment, the pharmaceutically acceptable salt is a succinate salt. In another embodiment, the pharmaceutically acceptable salt is a 2 -hydroxy succinate salt, e.g., an (5)-2- hydroxysuccinate salt. In another embodiment, the pharmaceutically acceptable salt is a hydrochloride salt (i.e., a salt with HC1). In another embodiment, the pharmaceutically acceptable salt is a malate salt, e.g., an L-malate salt.

[0168] The present disclosure also contemplates prodrugs of venglustat. The pharmaceutically acceptable prodrugs disclosed herein are derivatives which can be converted in vivo into venglustat. The prodrugs, which may themselves have some activity, become pharmaceutically active in vivo when they undergo, for example, solvolysis under physiological conditions or enzymatic degradation. Methods for preparing prodrugs of venglustat would be apparent to one of skill in the art based on the present disclosure.

[0169] In one embodiment, the carbamate moiety of venglustat is modified. For example, the carbamate moiety may be modified by the addition of water and / or one or two aliphatic alcohols. In this case, the carbon-oxygen double bond of the carbamate moiety adopts what could be considered a hemiacetal or acetal functionality. In one embodiment, the carbamate moiety may be modified by the addition of an aliphatic diol such as 1,2-ethanediol.

[0170] In one embodiment, the amino group on the quinuclidine moiety is modified. For example, the amino group may be modified to form an acid derivative or a quaternary ammonium salt. The derivative can be formed, for example, by reacting venglustat with an acetylating agent such as an acid chloride, or with an agent such as an alkyl halide. The present disclosure further embraces hydrates, solvates, and polymorphs of venglustat. For example, the venglustat may be in one or more crystalline forms as described in, e.g., international patent application No. PCT / US2014 / 027081 (published as WO 2014 / 152215), the entire content of which is incorporated by reference herein. In one embodiment, the venglustat is in the form of the crystalline Form A of the malate salt as described in PCT / US2014 / 027081.

[0171] Isotopically-labeled compounds are also within the scope of the present disclosure. As used herein, an “isotopically-labeled compound” refers to a presently disclosed compound including pharmaceutical salts and prodrugs thereof, each as described herein, in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds presently disclosed include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as2H,3H,13C,14C,15N,18O,17O,31P,32P,35S,18F, and36C1, respectively.

[0172] Pharmaceutical compositions

[0173] The present disclosure contemplates pharmaceutical compositions (e.g., oral pharmaceutical dosage forms) comprising venglustat, and at least one pharmaceutically acceptable excipient. Such compositions may be specifically adapted for use in any of the methods disclosed herein. In embodiments, a pharmaceutical composition for use in a method disclosed herein is a composition comprising 6 mg, or 15 mg of venglustat or a pharmaceutically acceptable salt thereof (calculated as the free base), and at least one pharmaceutically acceptable excipient, for use in a treatment method as described herein.

[0174] The pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington’s Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). Pharmaceutical compositions of the compounds presently disclosed may be preparedby conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable excipient.

[0175] In embodiments, the venglustat is in solid crystal form (e.g., crystalline malate salt Form A of venglustat). In other embodiments, the venglustat is in solid amorphous form. 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 wherein said dosage form comprises from about 2 to about 30 mg of venglustat (measured as the equivalent amount of free base), e.g., from about 4 mg to about 20 mg, or from about 8 mg to about 12 mg, or about 6 mg, or about 15 mg of venglustat (measured as the equivalent amount of free base).

[0176] In embodiments, the dosage form is a classic tablet or caplet (e.g., for swallowing), a chewable tablet, an orally disintegrating tablet, or a dispersible tablet.

[0177] In embodiments, the pharmaceutically acceptable excipient comprises one or more of (a) diluent / filler (e.g., cellulose or microcrystalline cellulose, mannitol, or lactose), (b) binder (e.g., povidone, methylcellulose, ethylcellulose, hydroxypropyl cellulose (such as low- substituted hydroxypropyl cellulose), or hydroxypropyl methylcellulose), (c) disintegrant (e.g., crospovidone, sodium starch glycolate, or croscarmellose sodium), (d) lubricant (e.g., magnesium stearate or sodium stearyl fumarate), (e) a glidant (e.g., silica or talc), (f) sweetener (e.g., sucralose, acesulfame potassium, aspartame, saccharine, neotame, or advantame), (g) flavor (e.g., apricot flavor), and (h) dye or colorant.

[0178] In embodiments, the pharmaceutically acceptable excipient comprises one or more hydrophilic water-soluble or water swellable polymers. In embodiments, the polymer is selected from the group consisting of natural or modified cellulosic polymers, or any mixture thereof.

[0179] In embodiments, any one or more pharmaceutically acceptable excipients are present in an amount of 0.01 to 80% by weight, e.g., 0.1 to 60%, or 0.1 to 40%, or 0.1 to 30%, 0.01 to 15%, orO.Ol to 10%, or O. l to 20%, or O.l to 15% or 0.1 to 10%, or 0.5 to 10%, or0.5 to 5%, or 1 to 5%, or 2.5 to 5%, or 1 to 3%, or 0.1 to 1% by weight. In embodiments, the dosage form comprises (a) from 5-95% by weight of diluent(s) / filler(s), e.g., 60-70% or 70-80%, or 65-75%, or 65-70%, or about 68%; (b) from 0.5-5% by weight of lubricant(s), e.g., 1-5%, or

[0180] 2-4%, or2-3%, or about 3%; (c) from 2-15% by weight of disintegrant(s), e.g., 4-12%, or 6- 10%, or 7-9%, or about 8%; (d) from 0-12% by weight of binder(s), e.g., 2-10%, or 2-8%, or

[0181] 3-7%, or 4-6%, or about 5%; (e) from 0-5% by weight of glidant(s), e.g., 0.15-4%, or 1-3%, or 1-2%, or about 1%; and (f) from 0-2% by weight of flavor(s), 0-2% by weight of sweetener(s) and / or 0-2% by weight of color(s), e.g., about 1% each of flavor(s), sweetener(s), and / or color(s). In embodiments, the venglustat is present in an amount of from 3% to 20% by weight (measured as free base), e.g., 5-15%, or 8-12%, or about 10% by weight (measured as free base), or is present in an amount of about 13% by weight of venglustat malate.

[0182] In embodiments, the dosage form is a tablet comprising a mixture of venglustat (e.g., venglustat malate) and one or more pharmaceutically acceptable excipients. In embodiments, the tablet is formed by direct compression of a mixture of venglustat (e.g., venglustat malate) and one or more pharmaceutically acceptable excipients.

[0183] In embodiments, the dosage form is a hard-shelled capsule, e.g., wherein said capsule contains a mixture of venglustat (e.g., venglustat malate) and one or more pharmaceutically acceptable excipients. The venglustat and other diluents / carriers may be comprised as granules or pellets, or as a powder, said granules, pellets, or powder being contained within the shell of the capsule.

[0184] In embodiments, the venglustat is present in (a) a mean particle size of 5 to 150 pm, e.g., 5 to 120 pm, 5 to 100 pm, 10 to 100 pm, 15 to 85 pm, 20 to 60 pm, 30 to 40 pm; and / or (b) a D90 of 120 pm or less, e.g., 50 to 100 pm, 70 to 90 pm, or 60 to 80 pm; and / or (c) a D10 of 30 pm or less, e.g. 10 to 25 pm, 10 to 20 pm or less, or 11 to 14 pm

[0185] A pharmaceutical composition or dosage form for use in accordance with the present disclosure can include an agent and another carrier, e.g., compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like. Carriers also include pharmaceutical excipients and additives, for example, proteins, peptides, amino acids, lipids, and carbohydrates (e.g., sugars, including monosaccharides, di-, tri-, tetra-, and oligosaccharides; derivatized sugars such as alditols, aldonic acids, esterified sugars, and the like; and polysaccharides or sugar polymers), which can be present singly or in combination, comprising alone or in combination 1 to 99.99% by weight or volume. Exemplary protein excipients include serum albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, and the like. Representative amino acid / antibody components, which can also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, and the like. Carbohydrate excipients are also intended within the scope of this disclosure, examples of which include but are not limited to monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), and myoinositol.

[0186] Carriers which may be used include a buffer or a pH adjusting agent; typically, the buffer is a salt prepared from an organic acid or base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride, or phosphate buffers. Additional carriers include polymeric excipients / additives such as polyvinylpyrrolidones, ficolls (a polymeric sugar), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-P- cyclodextrin), polyethylene glycols, flavoring agents, antimicrobial agents, sweeteners, antioxidants, antistatic agents, surfactants (e.g., polysorbates such as “TWEEN 20” and “TWEEN 80”), lipids (e.g., phospholipids, fatty acids), steroids (e.g., cholesterol), and chelating agents (e.g., EDTA).

[0187] The pharmaceutical compositions can be formulated so as to provide slow, extended, or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, and / or microspheres. The pharmaceutical compositions can also optionally contain opacifying agents and may be of a composition that releases the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner, e.g., by using an enteric coating. Examples of embedding compositions include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more pharmaceutically acceptable carriers, excipients, or diluents well known in the art (see, e.g., Remington’s). The compounds presently disclosed may be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,119,742; 3,492,397; 3,538,214; 4,060,598; and 4,173,626.

[0188] 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 starches, lactose, sucrose, glucose, mannitol, microcrystalline cellulose, calcium phosphate, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, pregelatinized maize starch, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, sucrose, and / or acacia; (3) humectants, such as glycerol; (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 retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, sodium lauryl sulphate, 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 glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets, and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of a similar type can also be prepared using fillers in soft and hard-filled gelatin capsules, and excipients such as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0189] A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactives, and / or dispersing agents. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, can optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the art.

[0190] In embodiments, the pharmaceutical compositions are administered orally in a liquid form. Liquid dosage forms for oral administration of an active ingredient include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. Liquid preparations for oral administration may be presented as a dry product for constitution with water or other suitable vehicle before use. In addition to the active ingredient, the liquid dosage forms can contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, the liquid pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents, and the like. Suspensions, in addition to the active ingredient(s) can contain suspending agents such as, but not limited to, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof. Suitable liquid preparations may be prepared by conventional means with a pharmaceutically acceptable additive(s) such as a suspending agent (e.g., sorbitol syrup, methyl cellulose, or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicle (e.g., almond oil, oily esters, or ethyl alcohol); and / or preservative (e.g., methyl or propyl p-hydroxybenzoates, or sorbic acid). The active ingredient(s) can also be administered as a bolus, electuary, or paste.

[0191] In some embodiments of the methods described herein, the pharmaceutical composition may take the form of tablets or lozenges formulated for buccal administration in a conventional manner.

[0192] In some embodiments of the methods described herein, the pharmaceutical compositions are administered by non-oral means such as by topical application, transdermal application, injection, and the like. In related embodiments, the pharmaceutical compositions are administered parenterally by injection, infusion, or implantation (e.g., intravenous, intramuscular, intra-arterial, subcutaneous, and the like).

[0193] In some embodiments of the methods described herein, the presently disclosed compounds may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain a formulating agent such as a suspending, stabilizing, and / or dispersing agent recognized by those of skill in the art. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. In some embodiments of the methods described herein, the pharmaceutical compositions can be in the form of sterile injections. The pharmaceutical compositions can be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. To prepare such a composition, 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 a suitable pH by addition of an appropriate amount of hydrochloric acid, sodium hydroxide or a suitable buffer, 1,3 -butanediol, Ringer’s solution, and isotonic sodium chloride solution. The pharmaceutical composition can also contain one or more preservatives, for example, methyl, ethyl, or n-propyl p-hydroxybenzoate. To improve solubility, a dissolution enhancing or solubilizing agent can be added or the solvent can contain 10-60% w / w of propylene glycol or the like.

[0194] In some embodiments of the methods described herein, the pharmaceutical compositions can contain one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions just prior to use. Such pharmaceutical compositionscan contain antioxidants; buffers; bacteriostats; solutes, which render the formulation isotonic with the blood of the intended recipient; suspending agents; thickening agents; preservatives; and the like.

[0195] Examples of suitable aqueous and nonaqueous carriers, which can be employed in any of the pharmaceutical compositions described herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, in order to prolong the effect of an active ingredient, it is desirable to slow the absorption of the compound from gastrointestinal administration, or from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the active ingredient then depends upon its rate of dissolution which, in turn, can depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered active ingredient may be accomplished by dissolving or suspending the compound in an oil vehicle. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0196] Controlled release parenteral compositions can be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated in biocompatible carrier(s), liposomes, nanoparticles, implants, or infusion devices. Materials for use in the preparation of microspheres and / or microcapsules include, but are not limited to, biodegradable / bioerodible polymers such as polyglactin, poly -(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L- glutamine), and poly(lactic acid). Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable, e.g., polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(gly colic acid), or poly(ortho esters).

[0197] In some embodiments of the methods described herein, for topical administration, a presently disclosed compound may be formulated as an ointment or cream. Presently disclosed compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0198] Kits and

[0199] The present disclosure further contemplates venglustat being packaged for release as a medicinal product, e.g. for use in the methods described herein. Such packaging will typically include instructions (e.g., on a label, a leaflet, or the like) for administering the medicinal product to subjects having hepatic impairment.

[0200] View from this aspect, the disclosure provides a method of providing venglustat, or a pharmaceutically acceptable salt thereof, wherein the venglustat, or pharmaceutically acceptable saltthereof, is provided along with information (e.g., on a label) that it is useful for treating subjects having hepatic impairment and that no dose adjustment is required in subjects having mild or moderate hepatic impairment. In embodiments, the method comprises, in accordance with the information (e.g., the information on the label), selecting a dose of venglustat, or pharmaceutically acceptable salt thereof, to be administered which is the same as the dose that would be administered to a subject not having hepatic impairment.

[0201] In a related aspect, the disclosure provides a package (or a kit) comprising venglustat, or a pharmaceutically acceptable salt thereof, and a label, wherein the label comprises a statement that venglustat, or a pharmaceutically acceptable salt thereof, is indicated for the treatment of subjects having mild or moderate hepatic impairment.

[0202] In embodiments, the label comprises a statement that the venglustat or pharmaceutically acceptable salt thereof should be administered as a once daily dose of 15 mg (measured as the free base). In embodiments, the label comprises a statement that the venglustat or pharmaceutically acceptable salt thereof should be administered as a once daily dose of 15 mg (measured as the free base) to subjects having mild or moderate hepatic impairment. In embodiments, the label comprises a statement that the venglustat or pharmaceutically acceptable salt thereof may be administered as a once daily dose of 6 mg (measured as the free base) to subjects having severe hepatic impairment.

[0203] In embodiments, the label comprises a statement that there is no effect of mild or moderate hepatic impairment on venglustat exposure, and / or that there is no clinically relevant change in venglustat exposure in subjects having mild or moderate hepatic impairment, and / or that no dose adjustment is required in subjects having mild or moderate hepatic impairment. In embodiments, the label comprises a statement that there is limited data on exposure of venglustat or a pharmaceutically acceptable salt thereof in subjects having severe hepatic impairment and / or that venglustat or a pharmaceutically acceptable salt thereof may be administered to subjects with severe hepatic impairment with caution.

[0204] Having been generally described herein, the follow non-limiting examples are provided to further illustrate the disclosure.

[0205] EXAMPLES

[0206] -4-yl)propan-2-

[0207] 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 hours, treated with an addition aliquot of ethyl 4-chloroacetoacetate (1 .0 mL, 7.4 mmol), and refluxed for an additional 3.5 hours. The reaction was then concentrated and the residue was partitioned between ethyl acetate (200 mL) and aqueous NaHCO3(200 mL). The organic layer was combined with a b ackextract of the aqueous layer (ethyl acetate, 1 x 75 mL), dried (Na2SO4), 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 colourless solid (13.58 g, 89%).

[0208] 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 frothy mixture was stirred for 15 minutes before cooling in an ice bath and adding iodomethane (4.4 mL, 71 mmol). The reaction was stirred overnight, allowing the cooling bath to slowly warm to room temperature. The mixture was then concentrated and the residue partitioned between ethyl acetate (80 mL) and water (200 mL). The organic layer was washed with a second portion of water (1 x 200 mL), dried (Na2SO4) 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)-2-methylpropanoate as a colourless oil (4.57 g, 66%).

[0209] 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 (l x 100 mL), acidified by the addition of 1.0 N HC1 (80 mL) and extracted with ethyl acetate (2 x 70 mL). The combined extracts were dried (Na2SO4) and concentrated to afford 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.

[0210] 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 another 1 hour before adding a solution of sodium azide (1.98 g, 30.5 mmol) in water (20 mL). 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 x 60 mL). The combined extracts were washed with aqueous NaHCO3 (1 x 150 mL) and brine (1 x 100 mL), dried (Na2SO4) and concentrated. After coevaporating with toluene (2 x 50 mL), the resulting white solid was taken up in toluene (100 mL) and refluxed for 4 hours. (S)-3-quinuclidinol (3.87 g, 30.4 mmol) was then added and reflux was continued overnight. The reaction was concentrated and the residue partitioned between ethyl acetate (100 mL) and aqueous NaHCO3(150 mL). The organic layer was washed with water (1 x 150 mL), dried (Na2SO4) and concentrated. The resulting off-white solid was purified by flash chromatography using a chloroform / methanol / ammonia gradient to afford the title compound as a white solid (4.34 g, 73%).XH NMR (400 MHz, CDC13) 8 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, HH) ppm.13C NMR (400 MHz, CDC13) 5 166.4, 165.1, 163.8 (d, 7=250.3 Hz), 162.9, 155.0, 130.1 (d, 7=3.3 Hz), 128.4 (d, 7= 8.5 Hz), 115.9 (d, 7= 22.3 Hz), 112.5, 71.2, 55.7, 54.2, 47.5, 46.5, 28.0, 25.5, 24.7, 19.6 ppm. Purity: 100 % UPLCMS (210 nm & 254 nm); retention time 0.83 min; (M+l) 390.

[0211] Example IB: Preparation of (7)-Quinuclidin-3 -yl (2-(2-(4-fhrorophenyl)thiazol-4-yl)propan-

[0212] 2-yl)carbamate (venglustat) in free base form

[0213] Step 1: Dimethylation with methyl iodide

[0214] Chemical Formula: C13H12FNO2S Chemical Formula: C15H16FNO2S Exact Mass: 265.06 Exact Mass: 293.09 Molecular Weight: 265.30 Molecular Weight: 293.36

[0215] A 3N RB flask was equipped with a thermometer, an addition funnel and a nitrogen inlet. The flask was flushed with nitrogen and potassium tert-butoxide (MW 112.21, 75.4 mmol, 8.46 g, 4.0 equiv., white powder) was weighed out and added to the flask via a powder funnel followed by the addition of THF (60 mL). Most of the potassium tert-butoxide dissolved to give a cloudy solution. This mixture was cooled in an ice-water bath to 0-2°C (internal temperature). 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 as rinse) and transferred to the addition funnel. This solution was added dropwise to the cooled mixture over a period of 25-30 min, keeping the internal temperature below 5°C during the addition. The reaction mixture was cooled back 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 already containing the clear colorless solution of methyl iodide in THF. This solution was added carefully dropwise to the dark brown reaction mixture over a period of 30-40 min, keeping the internal temperature below 10°C at all times during the addition. After the addition was complete, the slightly turbid mixture was stirred for an additional 1 h during which time the internal temperature dropped to 0-5°C. After stirring for an hour at 0-5°C, the reaction mixture was quenched with the slow dropwise addition of 5.0 M aqueous HC1 (8 mL) over a period of 5-7 min. The internal temperature was maintained below 20°C during this addition. After the addition, water (14 mL) was added and the mixture was stirred for 2-3 min. The stirring was stopped and the two layers were allowed to separate. The two layers were then transferred to a 250 mL IN RB flask and the THF was evaporated in vacuo as much as possible to obtain a biphasic layer of THF / product and water. The two layers were allowed to separate. A THF solution of the Step 1 product was used in the next reaction.

[0216] Step 2: Hydrolysis of the ethyl ester with LiOH monohydrate reflux, 16 h

[0217] Chemical Formula: C15H16FNO2S Chemical Formula: C13H12FNO2S

[0218] Exact Mass: 293.09 Exact Mass: 265.06

[0219] Molecular Weight: 293.36 Molecular Weight: 265.30

[0220] The crude ester in THF was added to the reaction flask. Separately, LiOH.H2O (MW 41.96, 75.0 mmol, 3.15 grams, 2.2 equiv.) was weighed out in a 100 mL beaker to which a stir bar was added. Water (40 mL) was added and the mixture was stirred until all the solid dissolved to give a clear colorless solution. This aqueous solution was then added to the 250 mL RB flask containing the solution of the ester in tetrahydro furan (THF). A condenser was attached to the neck of the flask and a nitrogen inlet was attached at the top of the condenser. The mixture was heated at reflux for 16 hours. After 16 hours, the heating was stopped and the mixture was cooled to room temperature. The THF was evaporated in vacuo to obtain a brown solution. An aliquot of the brown aqueous solution was analyzed by HPLC and LC / MS for complete hydrolysis of the ethyl ester. Water (15 mL) was added and this aqueous basic solution was extracted with TBME (2 x 40 mL) to remove the t-butyl ester. The aqueous basic layer was cooled in an ice-water bath to 0-10°C and acidified with dropwise addition of concentrated HC1 to pH ~ 1 with stirring. To this gummy solid in the aqueous acidic solution was added TBME (60 mL) and the mixture was shaken and then stirred vigorously to dissolve all the acid into the TBME layer. The two layers were transferred to a separatory funnel and the TBME layer was separated out. The pale yellow aqueous acidic solution was re-extracted with TBME (40 mL) and the TBME layer was separated and combined with the previous TBME layer. The aqueous acidic layer was discarded. The combined TBME layers are dried over anhydrousNa2SO4, filtered and evaporated in vacuo to remove TBME and obtain the crude acid as an orange / dark yellow oil that solidified under high vacuum to a dirty yellow colored solid. The crude acid was weighed out and crystallized by heating it in heptane / TBME (3 :1, 5 mL / g of crude) to give the acid as a yellow solid.

[0221] Step 3: Formation of hydroxamic acid with NH2OH.HCI

[0222] Chemical Formula: C13H12FNO2S Chemical Formula: C13H13FN2O2S Exact Mass: 265.06 Exact Mass: 280.07 Molecular Weight: 265.30 Molecular Weight: 280.32

[0223] The carboxylic acid (MW 265.3, 18.85 mmol, 5.0 g, 1 .0 equiv.) was weighed and transferred to a 25 mL IN RB flask under nitrogen. THF (5.0 mL) was added and the acid readily dissolved to give 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 a period of 10-15 minutes. The ice-bath was removed and the solution was stirred at room temperature for 1 h. After 1 h of stirring, the solution was again cooled in an ice-water bath to 0-2°C (bath temperature). Hydroxylamine hydrochloride (NH2OH.HC1; MW 69.49, 37.7 mmol, 2.62 g, 2.0 equiv.) was added slowly in small portions as a solid over a period of 3-5 minutes as this addition was exothermic. After the addition was complete, water (1.0 mL) was added to the heterogeneous mixture dropwise over a period of 2 minutes and the reaction mixture was stirred at 0-10°C in the ice-water bath for 5 minutes. The cooling bath was removed and the reaction mixture was stirred under nitrogen at room temperature overnight for 20-22 h. The solution became clear as all of the NH2OH.HC1 dissolved. 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 taken up in dichloromethane (120 mL) and water (60 mL). The mixture was transferred to a separatory funnel where it was shaken and the two layers allowed to separate. The water layer was discarded and the dichloromethane layer was washed with IN hydrochloride (HC1; 60 mL). The acid layer was discarded. The dichloromethane layer was dried over anhydrous Na2SO4, filtered and the solvent evaporated in vacuo to obtain the crude hydroxamic acid as a pale yellow solid that was dried under high vacuum overnight.

[0224] Step 3 continued: Conversion of hydroxamic acid to cyclic intermediate (not isolated)

[0225] Chemical Formula: C13H13FN2O2S Chemical Formula: CI4HI I FN2O3S Exact Mass: 280.07 Exact Mass: 306.05 Molecular Weight: 280.32 Molecular Weight: 306.31

[0226] The crude hydroxamic acid (MW 280.32, 5.1 g) was transferred to a 250 mL IN RB flask with a nitrogen inlet. A stir bar was added followed by the addition of acetonitrile (50 mL). The solid was insoluble in acetonitrile. The yellow heterogeneous mixture was stirred for 2-3 minutes under nitrogen and CDI (MW 162.15, 20.74 mmol, 3.36 g, 1.1 equiv.) was added in a single portion at room temperature. No exotherm was observed. The solid immediately dissolved and the clear yellow solution was stirred atroom temperature for 2-2.5 h. After 2- 2.5 h, an aliquot was analyzed by HPLC and LC / MS which showed conversion of the hydroxamic acid to the desired cyclic intermediate.

[0227] The acetonitrile was then evaporated in vacuo to give the crude cyclic intermediate as reddish thick oil. The oil was taken up in toluene (60 mL) and the reddish mixture was heated to reflux for 2 hours during which time, the cyclic intermediate released CO2and rearranged to the isocyanate (see below). Exact Mass: 306.05 Exact Mass: 262.06

[0228] Molecular Weight: 306.31 Molecular Weight: 262.30 Step 3 continued: Conversion of the isocyanate to the free base 13 11 2 2o243 2Exact Mass: 262.06 Exact Mass: 389.16

[0229] Molecular Weight: 262.30 Molecular Weight: 389.49

[0230] The reaction mixture was cooled to 50-60°C and (5 -(+)-quinuclidinol (MW 127.18, 28.28 mmol, 3.6 g, 1.5 equiv.) was added to the mixture as a solid in a single portion. The mixture was re-heated to reflux for 18 h. After 18 h, an aliquot was analyzed by HPLC and LC / MS which showed complete conversion of the isocyanate to the desired product. The reaction mixture was transferred to a separatory funnel and toluene (25 mL) was added. The mixture was washed with water (2 x 40 mL) and the water layers were separated. The combined water layers were re-extracted with toluene (30 mL) and the water layer was discarded. The combined toluene layers were extracted with IN HC1 (2 x 60 mL) and the toluene layer (containing the O-acyl impurity) was discarded. The combined HC1 layers were transferred to a 500 mL Erlenmeyer flask equipped with a stir bar. This stirring clear yellow / reddish orange solution was h asified to pH 10-12 by the dropwise addition of 50% w / w aqueous NaOH. The desired free base precipitated out of solution as a dirty yellow gummy solid which could trap the stir bar. To this mixture was added isopropyl acetate (100 mL) and the mixture was stirred vigorously for 5 minutes when the gummy solid went into isopropyl acetate. The 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, filtered into a pre-weighed RB flask and the solvent evaporated in vacuo to obtain the crude free base as beige to tan solid that was dried under high vacuum overnight.

[0231] Step 3 continued: Recrystallization of the crude free base

[0232] The beige to tan colored crude free base was weighed and re-crystallized from heptane / isopropyl acetate (3 : 1, 9.0 mL of solvent / g of crude free base). The appropriate amount of heptane / isopropyl acetate was added to the crude free base along with a stir bar and the mixture was heated to reflux for 10 min (free base was initially partially soluble but dissolved to give a clear reddish orange solution when heated to reflux). The heat source was removed and the mixture was allowed to cool to room temperature with stirring when a white precipitate formed. After stirring at room temperature for 3-4 h, the precipitate was filtered off under hose vacuum using a Buchner funnel, washed with heptane (20 mL) and dried under hose vacuum on the Buchner funnel overnight. The precipitate was the transferred to a crystallizing dish and dried at 55 °C overnight in a vacuum oven.1HNMR (400 MHz, CDC13) 5 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, 8.4 Hz, 1H), 3.05 - 2.19 (m, 5H), 2.0 - 1.76 (m, HH) ppm.13C NMR (100 MHz, CDC13) 8 166.38, 165.02, 162.54, 162.8-155.0 (d, C-F), 130.06, 128.43, 128.34, 116.01, 115.79, 112.46, 71.18, 55.70, 54.13, 47.42, 46.52, 27.94, 25.41, 24.67, 19.58 ppm. of crystalline forms of (A)-Quinuclidin-3-yl (2-(2-(4- l)propan-2- salts

[0233] Crystalline salts of (5)-Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2- yl)carbamate may be formed from the free base prepared as described in Example IB.

[0234] For example, the free base of (5 -Quinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan- 2-yl)carbamate (about 50 mmol) is dissolved IPA (140 ml) at room temperature and filtered. The filtrate is added into a 1 L round bottomed flask which is equipped with an overhead stirrer and nitrogen in / outlet. L-malic acid (about 50 mmol) is dissolvedin IPA (100 + 30 ml) at room temperature and filtered. The filtrate is added into the above 1 L flask. The resulting solution is stirred at room temperature (with or without seeding) under nitrogen for 4 to 24 hours. During this period of time crystals form. 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.

[0235] Crystal forms of other salts (e.g., acid addition salts with succinic acid or HC1) may be prepared in an analogous manner. Example 3 : Clinical study of venglustat in subjects having mild, moderate, and severe hepatic impairment

[0236] Study Design

[0237] This is a Phase 1 , open-label, four arm, parallel group, single dose, multicenter study with 15 mg of venglustat in participants having mild and moderate hepatic impairment, 6 mg of venglustat in participants having severe hepatic impairment, and in matched participants having normal hepatic function. The purpose of this study is to assess the effect of mild, moderate, and severe hepatic impairment on PK, safety, and tolerability of venglustat compared with normal hepatic function in male and female participants aged 18 to 79 years. A graphical depiction of the study design is shown in Figure 1.

[0238] Hepatic impairment is assessed according to the Child-Pugh classification. The criteria for a Child-Pugh scoring are described in the table below:

[0239] Points scored for observed findings

[0240] Clinical and biochemical 1 2 3 measurements

[0241] Encephalopathy grade none 1 to 2* 3 to 4**

[0242] Ascites absent Slight*** Moderate or severe****

[0243] Serum bilirubin, mg / dL <2 2 to 3 >3

[0244] Serum albumin, g / dL >3.5 2.8 to 3.5 <2.8

[0245] Prothrombin time, sec prolonged <4 (<1.7) 4 to 6 (1.7-2.2) >6 (>2.2)

[0246] Encephalopathy grade can be determined according to the following criteria:

[0247] Grade 0: normal consciousness, personality, neurological examination, electroencephalogram.

[0248] Grade 1 : restless, sleep disturbed, irritable / agitated, tremor, impaired handwriting, 5 cps waves.

[0249] Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.

[0250] Grade 3 : somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.

[0251] Grade 4: unarousable coma, no personality / behavior, decerebrate, slow 2 to 3 cps delta activity *or suppressed with medication

[0252] **or refractory.

[0253] Ascites can be graded according to the following criteria:

[0254] Absent: no ascites detectable by manual investigation

[0255] Slight: ascites palpation doubtful

[0256] Moderate: ascites detectable by palpation

[0257] Severe: necessity of paracentesis, dose not respond to medication treatment ***or subject on 1 medication to control ascites ****orsubject on 2 medications to control ascites

[0258] International normalized ratio of coagulation (INR) can be used as a substitute for prothrombin time (PT), with INR under 1.7 = 1 point, INR 1.7 to 2.2 = 2 points, INR above 2.2 = 3 points. PT and INR can be measured using standard assays, see e.g. Kitchen et al., 2021 (Int J Lab Hematol., 43(6): 1272- 283).

[0259] Based on the total score at inclusion (Day -1), subjects were classified as having: mild hepatic impairment (HI) if they had a total score of from 5 to 6; moderate HI if they had a total score of from 7 to 9; and severe HI if they had a total score of 10 or more. For each selected group (mild, moderate, and severe), approximately 8 participants were planned to be included in the study in order to have at least 6 evaluable participants in each group.

[0260] Matching of impaired and normal hepatic groups was based on gender, age, and body weight according to the table below, with control participants included after the enrolment of HI groups.

[0261] Step 1 = Gender

[0262] Participants having HI Matched participants

[0263] Participants having HI x male x / nb_hi_g = M male (rounded) sorted by gender y female y / nb_hi_h = F female (rounded)

[0264] “nb hi g”: Number of HI groups

[0265] Step 2 = Age

[0266] Male participants having a = % < 50 years old a * M = Mi male < 50 years old

[0267] HI sorted by age b = % > 50 years old b * M = M2male > 50 years old

[0268] (Note: Mi +2= M)

[0269] Female participants c = % < 50 years old c * F =Fi female < 50 years old having HI sorted by age d = % > 50 years old d * F = F2female > 50 years old

[0270] (Note: Fi + F2= F)

[0271] Convention: ifM 7 andM2or F}and F2have a value ofx.5, rounding up is done according to the most important group(s), e.g. the least represented group(s)

[0272] Step 3 = Weight

[0273] Participants having HI Average weight of Each matched male participant sorted by gender participants having HI is: weighs within 15% of Wm.

[0274] Wmfor male Each matched female participant

[0275] Wf for female weighs within 15% of Wf.

[0276] Participants in the control group and participants having mild or moderate hepatic impairment received a single dose of 15 mg venglustat (calculated as the free base, corresponding to approximately 20 mg of venglustat malate), and participants having severe hepatic impairment received a single dose of 6 mg venglustat (calculated as the free base, corresponding to approximately 8 mg of venglustat malate), on Day 1. Patients were institutionalized at least for the period from Day -1 to Day 5, inclusive, and were then discharged at the discretion of the investigators. To be conservative, a single oral venglustat dose of 6 mg was evaluated in participants having severe hepatic impairment. The half-life of venglustat is about 28.9 hours. However, since hepatic impairment can increase the half-life, participants having hepatic impairment had PK samples drawn up to 14 days after venglustat administration (i.e., 336 hours after administration) to capture at least 80% of AUC and allow for an accurate estimation of this PK parameter. Based on prior venglustat studies in healthy volunteers, participants having normal hepatic function did not need to undergo PK sampling after day 7 post-dose.

[0277] Blood samples were collected pre-dose and at approximately 1, 2, 3, 4, 6, 10, 12, 24, 48, 72, 96, 120, and 144 hours post-dose for all patients, and at 192, 240, 288, and 366 hours postdose for hepatically impaired patients. Venglustat plasma concentrations were determined using a validated liquid chromatography tandem mass spectrometry (LC-MS / MS) method (See, e.g., Peterschmitt etal., 2021, supra) with a lower limit of quantification (LLOQ) of 0.5 ng / mL. Due to the reduced dose of venglustat administered to participants having severe HI (6 mg instead of 15 mg), a dose adjustment was performed on PK parameters from severe HI participants, for linear regression.

[0278] The primary endpoint of the study was to investigate the effect of mild, moderate, and severe hepatic impairment on the main PK parameters of venglustat compared to normal hepatic function. The secondary endpoints were to study the effect of mild, moderate, and severe hepatic impairment on additional PK parameters of venglustat compared to normal hepatic function, and to assess the safety and tolerability of venglustat given as a single dose in participants having mild, moderate, and severe hepatic impairment compared with venglustat in matched participants having normal hepatic function. Measures of hepatic function (AST, ALT, alkaline phosphatase, gamma-glutamyl transferase, total and conjugated bilirubin) were also assessed.

[0279] Subjects were also monitored for any adverse events (reported by the subject or observed by investigators), and physical examination and clinical laboratory evaluations were conducted (hematology, biochemistry, coagulation, urinalysis). Subjects’ body weight, vital signs, and triplicate 12-lead electrocardiogram were recorded, and subjects underwent a drug screen, alcohol test, and SARS-CoV-2 testing.

[0280] For all safety data, the observation period was divided into 3 segments: (i) the pre-treatment period was defined as the period from informed consent signature up to the venglustat administration on Day 1 (excluded); (ii)the treatment-emergent (TE) period was defined as the period from the venglustat administration on Day 1 up to the EOS visit (included); and (iii) the post-treatment period was defined as the period from the end of the TE period. Inclusion / Exclusion Criteria

[0281] The inclusion criteria for patients with hepatic impairment included (but were not limited to):

[0282] • 18 to 79 years of age, inclusive;

[0283] • No significant abnormality in standard 12-lead ECG parameters; in no circumstances are participants with QTc (Fridericia) >480 ms enrolled;

[0284] • Stable chronic liver disease assessed by medical history, physical examination, and laboratory values; and

[0285] • Laboratory parameters within the acceptable range for patients with hepatic impairment; however, serum creatinine should be strictly at or below the upper laboratory norm and estimated glomerular filtration rate (eGFR) should be > 60 mL / min.

[0286] The inclusion criteria for healthy subjects included:

[0287] • 18 to 79 years of age, inclusive;

[0288] • No significant abnormality in standard 12-lead ECG parameters; in no circumstances are participants with QTc (Fridericia) >480 ms enrolled;

[0289] • Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination); and

[0290] • Laboratory parameters within the reference range for healthy participants.

[0291] The exclusion criteria for patients with hepatic impairment included:

[0292] • Uncontrolled clinically relevant cardiovascular, pulmonary, gastrointestinal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecological (if female), or infectious disease, or signs of acute illness;

[0293] • Severe course of COVID-19 (i.e., hospitalization, extracorporeal membrane oxygenation, mechanically ventilated) within 8 weeks prior to study enrolment;

[0294] • Hepatocellular carcinoma; acute hepatitis; uncontrolled or decompensated hepatic encephalopathy; encephalopathy Grade >2;

[0295] • History of current recreational drugs or alcohol abuse (alcohol consumption more than 40 g per day on a regular basis);

[0296] • Smoking more than 15 cigarettes or equivalent per day, unable to refrain from smoking over 8 cigarettes per day during the institutionalization; • Any drug(within 14 days before inclusion or within 5 times the elimination half-life or pharmacodynamic half-life of the medication) which could impact by any mechanism of action, the pharmacokinetics of the investigational medicinal product, including moderate and strong CYP3 A4 inhibitors or inducers;

[0297] • Participation in any other clinical study involving an IMP or in any other type of medical research within 14 days or 5 half-lives before screening, whichever is longer;

[0298] • Positive result on drug screen (amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates), unless this result is secondary to a documented medical prescription; positive alcohol test;

[0299] • Positive result on any of the following tests: anti- human immunodeficiency vims (HIV) Ab (or local test situation for anti -HIV1 / HIV2 Ab); CO VID-19 current infection at screening;

[0300] • Any consumption of citrus fruits (grapefruit, orange, etc.) or their juices within 5 days before inclusion; and

[0301] • Inability to comply with the following study restrictions: refraining from drinking alcohol, tea, coffee, chocolate, quinine, or caffeine-containing beverages from 1 day before institutionalization and throughout the study duration; following a stable lifestyle with no intensive physical activity from 1 day prior to institutionalization throughout the study duration until after collection of the final PK sample.

[0302] The exclusion criteria for healthy subjects included:

[0303] • Uncontrolled clinically relevant cardiovascular, pulmonary, gastrointestinal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecological (if female), or infectious disease, or signs of acute illness;

[0304] • Severe course of COVID-19 (i.e., hospitalization, extracorporeal membrane oxygenation, mechanically ventilated) within 8 weeks prior to study enrolment;

[0305] • Any history or presence of clinically relevant hepatic or renal disease;

[0306] • History of current recreational drugs or alcohol abuse (alcohol consumption more than 40 g per day on a regular basis);

[0307] • Smoking more than 15 cigarettes or equivalent per day, unable to refrain from smoking over 8 cigarettes per day during the institutionalization;

[0308] • Any medication (including St John’s Wort) within 14 days before inclusion or within 5 times the elimination half-life or pharmacodynamic half-life of the medication, with the exception of hormonal contraception ormenopausal hormone replacement therapy; any vaccination within the last 28 days and any biologies (antibody or its derivatives) given within 4 months before inclusion;

[0309] • Current enrollment OR past participation in another investigational study in which an investigational intervention (e.g., drug, vaccine, invasive device) was administered within the last 14 days or 5 half -lives days before screening, whichever is longer;

[0310] • Positive result on drug screen (amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates), unless this result is secondary to a documented medical prescription; positive alcohol test;

[0311] • Positive result on any of the following tests: anti- human immunodeficiency vims (HIV) Ab (or local test situation for anti-HIVl / HIV2 Ab), hepatitis B surface antigen (HBs Ag), anti -hepatitis B core antibodies (anti-HBb Ab), anti-hepatitis C virus (anti- HCV) antibodies, or COVID-19 current infection at screening; and

[0312] • Any consumption of citrus fruits (grapefruit, orange, etc.) or their juices within 5 days before inclusion; and

[0313] • Inability to comply with the following study restrictions: refraining from drinking alcohol, tea, coffee, chocolate, quinine, or caffeine-containing beverages from 1 day before institutionalization and throughout the study duration; following a stable lifestyle with no intensive physical activity from 1 day prior to institutionalization throughout the study duration until after collection of the final PK sample.

[0314] Patient Demographics and Study Intervention

[0315] 45 participants were screened with 26 participants enrolled and exposed to study intervention. The participants enrolled were: 8 having mild hepatic impairment; 8 having moderate hepatic impairment; 2 having severe hepatic impairment; and 8 having normal hepatic function.

[0316] Enrolled participants were defined as all screened participants who were allocated to a study intervention regardless of whether the study intervention was received or not. Participants who prematurely withdrew from the study may have been replaced if insufficient data for PK evaluations were obtained.

[0317] A total of 26 participants were enrolled and received a dose of venglustat. All participants were evaluable for safety assessment and PK parameters. Overall, 24 participants completed the study with 1 participant withdrawing consent on Day 15 in the moderate HI group while 1 participant in the severe HI cohort expired on Day 11 . Overall, 20 of 26 participants were male (14 participants having HI and 6 matched participants having normal hepatic function), 6 participants were female (4 participants having HI and 2 matched participants having normal hepatic function), the median (minimum-maximum) age at enrolment was 58.5 (31-71) years. Further information on baseline characteristics of the 26 participants are described in the table below. Overall, despite slight differences, the groups were considered comparable at baseline.

[0318] Table 1: Baseline characteristics — Safety population

[0319] Venglustat 15 Venglustat 15 Venglustat 6 Venglustat 15 mg All (N=26) mg mild HI mg moderate mg severe HI normal hepatic

[0320] (N=8) HI (N=8) (N=2) function (N=8)

[0321] Age (years)

[0322] Number 8 8 2 8 26

[0323] Mean (SD) 60.3 (6.7) 57.8 (12.5) 54.5 (19.1) 55.3 (8.9) 57.5 (9.9)

[0324] Median 62.0 57.5 54.5 58.0 58.5

[0325] Min ; Max 45 ; 67 31 ; 71 41; 68 35 ; 64 31 ; 71

[0326] Age group (years) [n (%)]

[0327] Number 8 8 2 8 26

[0328] From 18-64 years 7 (87.5) 5 (62.5) 1 (50.0) 8 (100) 21 (80.8)

[0329] From 65-79 years 1 (12.5) 1 (37.5) 1 (50.0) 0 5 (19.2)

[0330] Sex [n (%)]

[0331] Number 8 8 2 8 26

[0332] Male 6 (75.0) 6 (75.0) 2 (100) 6 (75.0) 20 (76.9)

[0333] Female 2 (25.0) 2 (25.0) 0 2 (25.0) 6 (23.1)

[0334] Ethnic Origin [n (%)]

[0335] Number 8 8 1 8 25

[0336] White 7 (87.5) 8 (100) 1 (50.0) 6 (75.0) 22 (84.6)

[0337] Black or African 1 (12.5) 0 0 2 (25.0) 3 (11.5)

[0338] American

[0339] Missing 0 0 1 (50.0) 0 1 (3.8)

[0340] Hispanic Ethnicity [n (%)]

[0341] Number 8 8 2 8 26

[0342] Hispanic or Latino 1 (12.5) 3 (37.5) 2 (100) 3 (37.5) 9 (34.6)

[0343] Not Hispanic or Latino 5 (62.5) 3 (37.5) 0 5 (62.5) 13 (50.0)

[0344] Not reported 2 (25.0) 2 (25.0) 0 0 4 (15.4)

[0345] Baseline Weight (kg)

[0346] Number 8 8 2 8 26

[0347] Mean (SD) 85.34 (15.83) 89.11 (16.47) 69.95 (15.63) 89.78 (12.58) 86.68 (15.10)

[0348] Median 90.85 87.45 69.95 92.25 88.50

[0349] Min ; Max 55.3 ; 103.8 64.0 ; 114.2 58.9 ; 81.0 66.5 ; 107.0 55.3 ; 114.2

[0350] Baseline BMI by category

[0351] (kg / m2)

[0352] Number 8 8 2 8 26

[0353] <18.5 0 1 (12.5) 0 0 1 (3.8)

[0354] 18.5 to <25 2 (25.0) 0 1 (50.0) 0 3 (11.5) Information on baseline Child-Pugh total score of the 18 participants having HI are described in Table 2 below.

[0355] Table 2: Child-Pugh at baseline — Safety population

[0356] Venglustat 15 mg Venglustat 15 mg Venglustat 6 mg severe mild HI (N=8) moderate HI (N=8) HI (N=2)

[0357] Encephalopathy Grade Number 8 8 2

[0358] Grade 0 - None 3 (37.5) 0 0

[0359] Grade 1 - 2 5 (62.5) 8 (100) 2 (100)

[0360] Ascites Number 8 8 2

[0361] Absent 8 (100) 0 0

[0362] Slight 0 5 (62.5) 2 (100)

[0363] Moderate 0 3 (37.5) 0

[0364] Serum total bilirubin (mg / dL)

[0365] Number 8 8 2

[0366] <2 8 (100) 8 (100) 0

[0367] 2 - 3 0 0 1 (50.0)

[0368] >3 0 0 1 (50.0)

[0369] Serum Albumin (g / dL)

[0370] Number 8 8 1

[0371] <2.8 0 0 1 (50.0)

[0372] 2.8 - 3.5 0 0 1 (50.0)

[0373] >3.5 8 (100) 8 (100) 0

[0374] Prothrombin Time, sec

[0375] Prolonged

[0376] Number 8 8 2

[0377] <4 6 (75.0) 5 (62.5) 0

[0378] >6 0 0 1 (50.0)

[0379] Missing 2 (25.0) 3 (37.5) 1 (50.0)

[0380] Prothrombin time, INR Number 8 8 2

[0381] <1.7 2 (25.0) 3 (37.5) 1 (50.0)

[0382] Missing 6 (75.0) 5 (62.5) 1 (50.0)

[0383] Child -Pugh Total Score Number 8 8 2

[0384] 5 3 (37.5) 0 0

[0385] 6 5 (62.5) 0 0

[0386] 7 0 5 (62.5) 0

[0387] 8 0 3 (37.5) 0

[0388] 10 0 0 1 (50.0)

[0389] 12 0 0 1 (50.0)

[0390] Child -Pugh Grade Number 8 8 2

[0391] A 8 (100) 0 0

[0392] B 0 8 (100) 0

[0393] C 0 0 2 (100) The 24 participants within the mild HI, moderate HI, and normal hepatic function groups all received a single oral dose of 15 mgvenglustatas the planned dose. The 2 participants in the severe HI group received a single oral dose of 6 mg venglustat as the planned dose. Results - Safety

[0394] Overall, 6 of 26 participants experienced a TEAE (3 [37.5%] participants in the mild HI group, 1 [50.0%] participant in the severe HI group, and 2 [25.0%] participants in the normal hepatic function group). There were no AESIs. One participant from the severe HI group experienced an SAE leading to death. This participant had a serious TEAE of sepsis which was considered as not related to venglustat administration.

[0395] Table 3: Treatment emergent adverse events — Safety population n (%) Venglustat 15 mg Venglustat 15 mg Venglustat 6 mg Venglustat 15 mg mild HI (N=8) moderate HI (N=8) severe HI (N=2) normal hepatic function (N=8)

[0396] Participants with any TEAE 3 (37.5) 0 1 (50.0) 2 (25.0)

[0397] Participants with any grade >= 0 0 1 (50.0) 0

[0398] 3 TEAE

[0399] Participants with any treatment 0 0 1 (50.0) 0 emergent SAE

[0400] Participants with any TEAE 0 0 1 (50.0) 0 leading to death

[0401] Participants with any TEAE 0 0 0 0 leading to permanent study discontinuation

[0402] Participants with any treatment 0 0 0 0 emergent AESI

[0403] TEAE = Treatment emergent adverse event; SAE = Serious adverse event; AESI = Adverse event of special interest; n (%) = number and percentage of participants with at least one TEAE.

[0404] Note: An adverse event is considered as treatment emergent if it occurred from the first investigational medicinal product (IMP) administration to the end of study visit (included).

[0405] The 3 (37.5%) participants in the mild HI group experienced the following TEAEs: 1 participant experienced a grade 1 mild bruise at a vessel puncture site, 1 participant experienced a grade 1 headache, and 1 participant had grade 2 fever and headache for 5 hours that responded to ibuprofen. All these events were considered as resolved and deemed as unrelated related to venglustat exposure.

[0406] The 2 (25.0%) participants in the normal hepatic function group each had 1 TEAE. 1 participant experienced 3 hours of grade 1 vertigo unrelated to venglustat exposure while 1 participant experienced 8 hours of mild headache that deemed related to venglustat exposure by the Investigator. Both events were considered as resolved.

[0407] There were no treatment-emergent PCSAs for laboratory parameters, vital signs, and ECG parameters across groups, that were considered clinically relevant by the Investigators. The participant having severe HI who experienced the grade 5 SAE had clinically significant alterations in laboratory parameters, vital signs, and ECG parameters at the hospital.

[0408] Results - Pharmacokinetics

[0409] Mean concentration-time profiles and key PK parameters were obtained in all participants from normal, mild, moderate, and severe HI groups (Figures 2 and 3).

[0410] Among the two severe participants, only partial PK parameters up to 144 hours post-dose could be accurately estimated in one of them. A summary of PK parameters is presented in the table below.

[0411] Table 4: Mean ± SI) (geometric mean) [CV° / o] pharmacokinetic parameters for venglustat following a single oral administration of venglustat in participants having normal hepatic function, and mild, moderate, and severe hepatic impairment

[0412] PK parameters Normal Hepatic Mild Hepatic Moderate Hepatic Severe Hepatic

[0413] Function (15 mg) Impairment (15 mg) Impairment (15 mg) Impairment (6 mg)

[0414] N 8 8 8 2

[0415] Cmax (ng / mL) 64.9 ± 23.1 54.4 ± 21.0 48.6 ± 23.2 10.1 ± 2.79

[0416] (61.8)

[0036] (51.0)

[0039] (44.2)

[0048] (9.94)

[0028] tmax“ 3.00 3.50 5.05 4.54

[0417] (1.00, 4.00) (2.00, 6.00) (1.00, 12.00) (3.00, 6.08)

[0418] AUCo-i44h (ng*h / mL) 2750 ± 995 2810 ± 880 2820 ± 1090 628 ± 221

[0419] (2620)

[0036] (2690)

[0031] (2650)

[0039] (608)

[0035]

[0420] AUCiast (ng*h / mL) 2760 ± 992 3280 ± 1250 3400 ± 1220 514*

[0421] (2620)

[0036] (3100)

[0038] (3210)

[0036]

[0422] AUC (ng*h / mL) 3040 ± 1170 3370 ± 1350 3520 ± 1220 554c

[0423] (2880)

[0038] (3170)

[0040] (3330)

[0035] ti / 2z (h) 40.8 ± 6.91 51.9 ± 15.1 64.0 ± 20.4 60.3 ± 11.4

[0424] (40.3)

[0017] (50.2)

[0029] (60.8)

[0032] (59.8)

[0019]

[0425] CL / F (L / h) 5.48 ± 1.68 5.00 ± 1.67 4.77 ± 1.72 10.8C

[0426] (5.22)

[0031] (4.73)

[0033] (4.50)

[0036]

[0427] Vss / F (L) 306 ± 74.0 354 ± 119 415 ± 176 814c

[0428] (298)

[0024] (337)

[0034] (380)

[0042]

[0429] Rac,pred 3.08 ± 0.566 3.80 ± 1.15 4.33 ± 1.27 3.93c

[0430] Total variability (based on CV%) in plasma venglustat Cmax, AUCiast, and AUC was generally moderate (28% to 48%). For participants having normal hepatic function, mild, moderate, and severe HI respectively, the mean apparent clearance was 5.48 L / h, 5.00 L / h, 4.77 L / h and 10.8 L / h, with ti / 2Zof 40.8 hours, 51.9 hours, 64.0 hours, and 60.3 hours.

[0431] The clearance (10.8 L / h) estimated for one severe HI participant was associated to a lower exposure than the other severe participant (1 .48-fold and 1.67 -fold lower Cmaxand AUC0-i44h, respectively).

[0432] The statistical analysis of effect of mild and moderate HI on venglustat PK parameters compared to participants having normal hepatic function is presented in the table below.

[0433] Table 5: Point estimates of population ratio with 90% CI for venglustat PK parameters

[0434] Comparison Parameter Point estimate 90% CI

[0435] Moderate HI vs normal control Cmax 0.72 (0.51 to 1.00)

[0436] Mild HI vs normal control 0.82 (0.59 to 1.15)

[0437] Moderate HI vs normal control AUCiaSt1.22 (0.91 to 1.65)

[0438] Mild HI vs normal control 1.18 (0.88 to 1.59)

[0439] Moderate HI vs normal control AUC 1.16 (0.85 to 1.58)

[0440] Mild HI vs normal control 1.10 (0.81 to 1.51)

[0441] Moderate HI vs normal control CL / F 0.86 (0.63 to 1.18)

[0442] Mild HI vs normal control 0.91 (0.66 to 1.24)

[0443] Moderate HI vs normal control Vss / F 1.28 (0.94 to 1.73)

[0444] Mild HI vs normal control 1.13 (0.84 to 1.53)

[0445] Moderate HI vs normal control ti / 2z 1.51 (1.19 to 1.91)

[0446] Mild HI vs normal control 1.24 (0.99 to 1.57)

[0447] HI = hepatic impairment

[0448] A statistical significance between HI participants and participants having normal hepatic function was not observed on PK parameters (all 90% CI included 1), except for apparent terminal half-life for moderate HI with a 1.51-fold increase (90% CI: 1.19-1.91). Severely impaired participants were not included in the statistical analysis due to the low number of participants. However, when normalized by dose, exposure parameters (Cmaxand AUCo-i44h) of both participants remained similar to exposure observed in participants having normal hepatic function. Conclusions

[0449] Following a single 15 mg dose of venglustat, no effect of moderate or mild HI was observed on PK exposure parameters. Venglustat AUC was similar in mild (Point estimate ratio: 1.10 ; 90% CI : 0.81-1.51) and moderate groups (Point estimate ratio:1.16 ; 90% CI : 0.85-1.58), with a similar or slight decrease of Cmaxin the mild (Point estimate ratio: 0.82 ; 90% CI : 0.59-1.15) and moderate group (Point estimate ratio: 0.72 ; 90% CI : 0.51-1.00), respectively.

[0450] No conclusion can be provided for severe HI participants receiving 6 mg of venglustat, due to low sample size. However, no trend for increased exposure normalized by the dose was observed.

[0451] Overall, a single oral dose of 15 mg of venglustat was generally safe and well tolerated in both groups of participants having mild and moderate HI and of matched control participants having normal hepatic function. One death considered non-drug-related occurred in the severe HI group. Safety and tolerability conclusions of a single oral dose of 6 mg of venglustat in participants having severe HI are limited by the low number of participants enrolled.

[0452] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages, and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

[0453] In addition, where features or aspects are described in terms of Markush groups, those skilled in the art will recognize that such features or aspects are also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0454] 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 incorporated by reference individually. In case of conflict, the present specification, including definitions, will control.

Claims

1. CLAIMS1. A method for treating a disease or disorder in a subject having impaired hepatic function, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the impaired hepatic function is mild, moderate, or severe hepatic impairment.

3. The method of claim 1 or claim 2, wherein the impaired hepatic function is of class A, B, or C according to the Child-Pugh Score.

4. A method for treating a disease or disorder in a subject having mild or moderate hepatic impairment, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the hepatic impairment is of class A or B according to the Child-Pugh Score.

6. The method of claim 4 or claim 5, wherein the venglustat or pharmaceutically acceptable salt thereof is administered at a dose that would be administered to a subject having the same disease or disorder but not having impaired hepatic function.

7. The method of any one of claims 4 to 6, wherein the venglustat or pharmaceutically acceptable salt thereof is administered at a dosage of 15 mg per day (calculated as the free base).

8. A method for treating a disease or disorder in a subject having severe hepatic impairment, the method comprising administering to the subject in need thereof an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

9. The method of claim 8, wherein the venglustat or pharmaceutically acceptable salt thereof is administered at a dosage of 6 mg per day (calculated as the free base).

10. The method of any one of claims 1 to 9, wherein 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., autosomal dominant polycystic kidney disease (ADPKD), or autosomal recessive polycystic kidney disease (ARPKD)), and a ciliopathy (e.g., Bardet-Biedl syndrome).

11. The method of claim 10, wherein the disease or disorder is a lysosomal storage disease.

12. The method of claim 11, wherein the method further comprises administering to the subject an effective amount of a lysosomal enzyme.

13. The method of claim 11 or claim 12, wherein the disease or disorder is Gaucher disease (e.g., Gaucher disease type 3), optionally wherein the lysosomal enzyme is glucocerebrosidase.

14. The method of claim 11 or claim 12, wherein the disease or disorder is Fabry disease, optionally wherein the lysosomal enzyme is alpha-galactosidase.

15. The method of any one of claims 1 to 14, wherein the subject is not concurrently being administered a CYP3 A inhibitor (e.g. a strong CYP3 A4 inhibitor).

16. Venglustat or a pharmaceutically acceptable salt thereof, for use in a method according to any one of claims 1 to 15.

17. Venglustat or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a subject having impaired hepatic function.

18. Venglustat or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder in a subject having mild or moderate hepatic impairment.

19. Venglustat or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder in a subject having severe hepatic impairment.

20. A method of providing venglustat, or a pharmaceutically acceptable salt thereof, wherein the venglustat, or pharmaceutically acceptable salt thereof, is provided along with information that it is useful for treating subjects having hepatic impairment and that no dose adjustment is required in subjects having mild or moderate hepatic impairment.

21. The method of claim 20, wherein in accordance with the information the method comprises selecting a dose of venglustat, or pharmaceutically acceptable salt thereof, to be administered which is the same as the dose that would be administered to a subject not having hepatic impairment.

22. A package comprising venglustat, or a pharmaceutically acceptable salt thereof, and a label, wherein the label comprises a statement that venglustat, or a pharmaceutically acceptable salt thereof, is indicated for the treatment of subjects having mild or moderate hepatic impairment.

23. The package of claim 22, wherein the label comprises a statement that the venglustat or pharmaceutically acceptable salt thereof should be administered as a once daily dose of 15 mg (measured as the free base).

24. The package of claim 22 or claim 23, wherein the label comprises a statement that there is no effect of mild or moderate hepatic impairment on venglustat exposure, and / or that there is no clinically relevant change in venglustat exposure in subjects having mild or moderate hepatic impairment, and / or that no dose adjustment is required in subjects having mild or moderate hepatic impairment.

25. The package of any one of claims 22 to 24, wherein the label comprises a statement that there is limited data on exposure of venglustat or a pharmaceutically acceptable salt thereof in subjects having severe hepatic impairment, and / or that venglustat or a pharmaceutically acceptable salt thereof may be administered to subjects with severe hepatic impairment with caution.

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