Venglustat for use in methods for reducing disease related biomarker levels in patients with ganglioside storage disorders

Abstract

Provided herein is a method of stabilizing the 9-HPT, 25-FWT, and / or FARS-neuro test score (a measure of neurologic impairment) in a human subject suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis. The method comprises administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

Description

[0001] VENGLUSTAT FOR USE IN METHODS FOR REDUCING DISEASE RELATED BIOMARKER LEVELS

[0002] IN PATIENTS WITH GANGLIOSIDE STORAGE DISORDERS

[0003] Provided herein is a method of stabilizing the 9-HPT, 25-FWT, and / or FARS-neuro test score (a measure of neurologic impairment) in a human subject suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis. The method comprises administering to the

[0004] 5 subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

[0005] BACKGROUND

[0006] GM1 and GM2 gangliosidoses are ultra-rare, progressive autosomal recessive lysosomal storage disorders with no currently approved treatments. Each condition presents with a constellation of symptoms and severities, but is typically characterised by three subtypes: an acute infantile form (in which symptoms typically emerge in the first 6 months of life), a subacute juvenile form (in which symptoms typically emerge between the ages of 1 and 10), and a chronic adult form. The juvenile form typically differs from the adult form in the impact of the disease on cognitive function (see, e.g., Maegawa et al., Pediatrics (2006) 118(5) :e 1550— e 1562; and Nicoli et al., Frontiers in Genetics (2021) 12:el— el 1).

[0007] 15 Both GM1 and GM2 gangliosidoses arise due to pathogenic variants of genes encoding for enzymes involved in the glycosphingolipid pathway, and both lead to accumulation of glycosphingolipids in cells of the affected subject, in particular in neuronal cells. GM2 gangliosidosis typically results from pathogenic mutations in the HEXA and / or HEXB genes, leading to a deficiency in the enzyme P-hexosaminidase A (Tay-Sachs variant) or a combined

[0008] 20 deficiency of -hexosaminidase A and B (Sandhoff variant). In each case, affected individuals are impaired in lysosomal degradation of the GM2 ganglioside and other glycolipids, causing accumulation of these in the lysosomes of cells and elsewhere in the body. This accumulation causes cytotoxic effects, especially in neurons, which leads to progressive neurological impairment including motor deficits, progressive weakness,

[0009] 25 hypotonia, decreased responsiveness, vision deterioration, and seizures. GM1 gangliosidosis is caused by mutations in p-galactosidase, encoded by the GLB1 gene, which leads to the accumulation of GM1 ganglioside and its asialo derivative GAI, primarily in lysosomes of neuronal tissue. Clinical symptoms include hepatosplenomegaly, cardiomyopathy, skeletal disease, and seizures, especially in early onset forms of the disease.

[0010] Sialidosis is another ultra-rare autosomal recessive lysosomal storage disorder. It is caused by a deficiency in the enzyme neuraminidase- 1 (typically due to mutations in the NEU1 gene) which leads to progressive accumulation of oligosaccharides and sialylated glycoproteins in cells (see, e.g., Khan and Sergi, Diagnostics (2018) 8(2):29). Type I sialidosis is a less severe subtype of the disease which is characterised by gait abnormalities, decreased visual acuity,

[0011] 35 or both. Action myoclonus, intentional tremors, cerebellar ataxia, and hyperreflexia are the other commonly found symptoms. Type II sialidosis is the more severe subtype which is characterised by hydrops fetalis, hepatomegaly and stillbirths or death at a very early age (congenital form) and by visceromegaly, skeletal abnormalities, mental retardation, ocular disorders, hearing loss, ataxia and seizures (infantile / juvenile form). There is no approved treatment for sialidosis.

[0012] Several potential approaches have been suggested for the treatment of lysosomal storage disorders, including enzyme replacement therapy (“ERT”, in which a functioning version of the deficient enzyme is injected into the patient), substrate reduction therapy (“SRT”, in which agents, typically small molecule drugs, are administered to modulate the glycosphingolipid pathway in a bid to reduce the accumulation of storage lipids), pharmacological chaperone therapy (in which agents are administered to assist in proper protein folding and trafficking to the lysosome), gene therapy (in which functional versions of the deficient genes are introduced into the patient), and stem cell therapy (in which haematopoietic stem cells are transplanted into the patient). However, no therapeutic treatment for GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis has yet been approved.

[0013] Venglustat (also known as (.S)-quiniiclidin-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 lysosomal storage diseases such as Gaucher disease and Fabry disease (See, e.g., WO 2012 / 129084, the content of which is hereby incorporated by reference in its entirety). It has been suggested that venglustat, which is an inhibitor of the enzyme glucosylceramide synthase (GCS), might act in these treatments by reducing levels of the glycosphingolipid GL1. Early phase clinical studies have shown that venglustat exhibits an acceptable safety profde when administered in dosages of up to around 15 mg per day to healthy individuals (see, e.g., Peterschmitt et al., Clin Pharmacol Drug Dev (2021) 10( 1): 86— 98). The impact of venglustat in human patients with GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis has not been reported.

[0014] In the absence of any authorised treatment options, there is an urgent need for agents which can manage the progression of symptoms in subjects with GM1 gangliosidosis juvenile GM2 gangliosidosis, or sialidosis, in particular the progressive neurologic dysfunction which is associated with those conditions.

[0015] SUMMARY

[0016] The present disclosure describes the results of clinical studies which monitored the impact of venglustat in human patients with GM1 gangliosidosis or juvenile GM2 gangliosidosis. Without wishing to be bound by theory, it is postulated that venglustat may be capable of stabilising neurologic function in the patient, such that the progression of the disease can be better managed, e.g. such that motor impairment can be stabilised or delayed. This hypothesis is consistent with the results of the study which are presented below, and is also consistent with the observation made during that study that the level of the primary storage lipid (GM1 or GM2) is markedly reduced in the CSF and plasma of patients to whom venglustat is administered. The present application is thus directed to methods in which venglustat is administered to a human patient with GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, such that measures of neurologic function in the patient may be stabilised.

[0017] Accordingly, in a first aspect the disclosure provides a method of stabilizing the 9-HPT, 25- FWT, and / or FARS-neuro test score in a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

[0018] In another aspect, the disclosure provides a method of administering venglustat, or a pharmaceutically acceptable salt thereof, to a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, wherein the venglustat or pharmaceutically acceptable salt thereof is administered in an effective amount to stabilize the 9-HPT, 25-FWT, and / or FARS-neuro test score of the subject.

[0019] In embodiments, the change in 9-HPT score from baseline is less than about 20%, or the change in 9-HPT score from baseline ranges from about -10% to about +10% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the 9-HPT score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

[0020] In embodiments, the change in 25-FWT score from baseline is less than about 30% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer), or the change in 25-FWT score from baseline ranges from about -20% to about +20% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the 25-FWT score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

[0021] In embodiments, the change in FARS-neuro score from baseline is less than about 5 points over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer), or the change in FARS-neuro score from baseline ranges from about -10 points to about +10 points over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the FARS-neuro score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

[0022] In embodiments, the subject suffers from GM1 gangliosidosis. In embodiments, administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age ranging from 2 to 19 years old. In embodiments, the subject experienced onset of symptoms at an age ranging from 1 to 7 years old, and / or the subject was diagnosed as having GM1 gangliosidosis at an age ranging from 2 to 15 years old. In embodiments, the subject suffers from juvenile GM2 gangliosidosis (e.g., wherein the juvenile GM2 gangliosidosis is the Tay-Sachs variant or the Sandhoff variant). In embodiments, administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age ranging from 4 to 16 years old. In embodiments, the subject experienced onset of symptoms at an age ranging from 1 to 7 years old, and / or the subject was diagnosed as having GM2 gangliosidosis at an age ranging from 4 to 13 years old.

[0023] In embodiments, the subject suffers from sialidosis (e.g., Type I sialidosis). In embodiments, the change in 9-HPT score from baseline is less than 0% (i.e., negative) over a period of venglustat administration of at least 104 weeks. In embodiments, the change in FARS-neuro score from baseline is less than 0 points (i.e., decreases) over a period of venglustat administration of at least 104 weeks.

[0024] In embodiments, the venglustat or pharmaceutically acceptable salt thereof is administered orally, e.g. in the form of a tablet or capsule. In embodiments, the venglustat or pharmaceutically acceptable salt thereof is administered once daily.

[0025] In embodiments, the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage (calculated as the free base) of:

[0026] (a) about 15 mg per day to a subject having a body weight of > 50 kg;

[0027] (b) about 12 mg per day to a subject having a body weight of 30 kg to < 50 kg;

[0028] (c) about 6 mg per day to a subject having a bodyweight of 15 kg to < 30 kg; or

[0029] (d) about 4 mg per day to a subject having a bodyweight of 10 kg to < 15 kg.

[0030] In embodiments, the venglustat is in the form of venglustat free base, or a pharmaceutically acceptable salt of venglustat, optionally venglustat L-malate salt.

[0031] In another aspect, the disclosure provides venglustat, or a pharmaceutically acceptable salt thereof, for use in a method as defined hereinbefore.

[0032] In another aspect, the disclosure provides use of venglustat, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method as defined hereinbefore.

[0033] Additional features and advantages of the methods disclosed herein will be apparent from the following detailed description.

[0034] BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Fig. 1 shows a part of the glycosphingolipid pathway, highlighting the relationship between various ganglioside glycosphingolipids (GM1, GM2, GM3), the enzymes which are responsible for the processing of those glycosphingolipids and diseases which arise as a result of mutations in the corresponding genes.

[0036] Fig. 2 shows the percent change in 9-HPT score over the course of the study in patients with GM1 gangliosidosis or juvenile GM2 gangliosidosis who were administered venglustat. Fig. 3 shows the percent change in 25-FWT score over the course of the study in patients with GM1 gangliosidosis or juvenile GM2 gangliosidosis who were administered venglustat.

[0037] Fig. 4 shows the percent change in FARS-neuro score over the course of the study in patients with GM1 gangliosidosis or juvenile GM2 gangliosidosis who were administered venglustat.

[0038] DETAILED DESCRIPTION

[0039] 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.

[0040] Definitions

[0041] 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.

[0042] The practice of the present disclosure will employ, unless otherwise indicated, conventional techniques of tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the skill of the art.

[0043] 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.

[0044] 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”. 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’.

[0045] A “subject”, “individual”, or “patient” is used interchangeably herein, and refers to a human.

[0046] The term “healthy individual” as used herein typically denotes an individual who does not suffer from a condition which is responsive to venglustat administration. In particular, a healthy individual may be an individual who does not suffer from a lysosomal storage disease selected from a GM2 gangliosidosis (e.g., juvenile GM2 gangliosidosis) and GM1 gangliosidosis. A healthy individual typically does not have any GBA mutations and typically also lacks pathogenic mutations in other genes encoding enzymes involved in the glycosphingolipid pathway, for example P-hexosaminidase (e.g., Hex A or Hex B), GM1- - galactosidase, GM2 ganglioside activator protein, and neuraminidase.

[0047] “Administering” is defined herein as a means of providing an agent (e.g., active ingredient) or a composition containing the agent to a subject in a manner that results in the agent being inside the subject’s body, or prescribing, instructing, managing, or supervising another, including the subject, to so provide said agent or composition. 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.

[0048] The term “treating” or “treatment” of a subject as used herein will typically refer to interventions having a therapeutic or prophylactic effect, e.g., as indicated by some degree of clinical response over a particular timescale (e.g., 104 weeks). The terms “treating” or “treatment” may also, however, include interventions which do not have a measurable or quantifiable clinical response over a particular timescale (e.g., 104 weeks). To the extent that the treatment has a measurable therapeutic or prophylactic effect on a disease, the “treating” or “treatment” of the disease includes: (1) inhibiting the disease, i.e. arresting or reducing the development of the disease or its clinical symptoms; and / or (2) relieving the disease, i.e. causing regression of the disease or its clinical symptoms. “Preventing” or “prevention” of a disease includes causing the clinical symptoms of the disease not to develop in a patient that may be predisposed to the disease but does not yet experience or display symptoms of the disease. A disease which is “amenable to treatment” with or “treatable by” a particular active agent is a disease which can be treated and / or prevented by the active agent in at least some patients who are suffering from the disease or who are predisposed to the disease.

[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.

[0050] 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, e.g., the time period over which each individual dosage is to be administered, 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 from in 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 plasma, serum, or CSF level commensurate with the concentrations found to be effective in vitro. Determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. Consistent with this definition, as used herein, the term “therapeutically effective amount” is an amount sufficient to modulate (e.g., improve) one or more symptoms associated with a disease or disorder described herein, ex vivo, in vitro, or in vivo.

[0051] 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 or water / 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 (20th ed., Mack Publishing Co. 2000).

[0052] 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.

[0053] 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. 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- malate.

[0054] 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.

[0055] 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.

[0056] Any compositions or methods provided herein can be combined with one or more of any of the other compositions and methods provided herein.

[0057] The following abbreviations are used herein: 25-FWT 25-foot timed walk test (also T25-FW) 9-HPT 9-hole peg test CDI 1 , 1' -carbonyldiimidazole CSF cerebrospinal fluid DMF dimethylformamide ECG electrocardiogram EDTA ethylenediaminetetraacetic acid ERT enzyme replacement therapy FARS-neuro neurological component of the Friedreich Ataxia Rating Scale GAI asialo-monosialotetrahexosyl ganglioside GBA glucocerebrosidase GCS glucosylceramide synthase GLB1 P-galactosidase gene GL1 glucosylceramide (also GL-1) GM1 monosialotetrahexosyl ganglioside GM2 ganglioside monosialic 2 GM3 monosialodihexosyl ganglioside Hex P-hexosaminidase HEXA / B P-hexosaminidase A / B gene HPC hydroxypropylcellulo se HPLC high performance (or high pressure) liquid chromatography HSA human serum albumin IPA isopropyl alcohol NEU1 neuraminidase- 1 gene Q.S. a sufficient quantity

[0058] RB round bottomed rHA recombinant human albumin SRT substrate reduction therapy TBME methyl tert-butyl ether THF tetrahydrofuran UPLCMS ultra-performance liquid chromatography-mass spectrometry

[0059] Methods applied to subjects with GM1 gangliosidosis, juvenile GM2 gangliosidosis or sialidosis

[0060] 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). Venglustat is an oral GCS inhibitor under development for the treatment of conditions including Fabry disease and Gaucher disease.

[0061] The present disclosure and the Examples which follow describe the results of a clinical study in which venglustat was administered to human subjects suffering from GM1 gangliosidosis, a juvenile GM2 gangliosidosis, or sialidosis. Patients receiving venglustat showed, on average, a stabilisation of neurologic function over the two year treatment period, as assessed by the 9-HPT, 25-FWT, and FARS-neuro test.

[0062] Accordingly, in one aspect the disclosure provides a method of stabilizing the 9-HPT, 25- FWT, and / or FARS-neuro test score in a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof.

[0063] In a related aspect, the disclosure provides venglustat, or a pharmaceutically acceptable salt thereof, for use in a method of stabilizing the 9-HPT, 25-FWT, and / or FARS-neuro test score in a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis. The disclosure also provides venglustat, or a pharmaceutically acceptable salt thereof, for use in a method as defined herein (e.g., as claimed in the appended claims).

[0064] In another related aspect, the disclosure provides the use of venglustat, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of stabilizing the 9-HPT, 25-FWT, and / or FARS-neuro test score in a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis. The disclosure also provides the use of venglustat, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method as defined herein (e.g., as claimed in the appended claims).

[0065] In another aspect, the disclosure provides a method of administering venglustat, or a pharmaceutically acceptable salt thereof, to a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, wherein the venglustat or pharmaceutically acceptable salt thereof is administered in an effective amount to stabilize the 9-HPT, 25-FWT, and / or FARS-neuro test score of the subject.

[0066] In another aspect, the disclosure provides a method of slowing or stopping the progression of neurologic dysfunction in a subject in need thereof as assessed by the 9-HPT, the 25-FWT, and / or the FARS-neuro test, wherein the subject is a human subject suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof. In a related aspect, the disclosure provides venglustat, or a pharmaceutically acceptable salt thereof, for use in a method of slowing or stopping the progression of neurologic dysfunction in a subject in need thereof as assessed by the 9-HPT, the 25-FWT, and / or the FARS-neuro test, wherein the subject is a human subject suffering from GM1 gangliosidosis juvenile GM2 gangliosidosis, or sialidosis. In a further related aspect, the disclosure provides the use of venglustat, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of slowing or stopping the progression of neurologic dysfunction in a subject in need thereof as assessed by the 9-HPT, the 25-FWT, and / or the FARS-neuro test, wherein the subject is a human subject suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis.

[0067] In another aspect, the disclosure provides a method of administering venglustat, or a pharmaceutically acceptable salt thereof, to a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, wherein the venglustat or pharmaceutically acceptable salt thereof is administered in an effective amount to slow or stop the progression of neurologic dysfunction in the subject as assessed by the 9-HPT, the 25-FWT, and / or the FARS-neuro test.

[0068] In a related aspect, the disclosure provides a method of stabilizing neurological function in a subject in need thereof as assessed by the 9-HPT, the 25-FWT, and / or the FARS-neuro test, wherein the subject is a human subject suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof. In another related aspect, the disclosure provides venglustat, or a pharmaceutically acceptable salt thereof, for use in a method of stabilizing neurological function in a subject in need thereof as assessed by the 9- HPT, the 25-FWT, and / or the FARS-neuro test, wherein the subject is a human subject suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis. In another related aspect, the disclosure provides the use of venglustat, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of stabilizing neurological function in a subject in need thereof as assessed by the 9-HPT, the 25-FWT, and / or the FARS-neuro test, wherein the subject is a human subject suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis.

[0069] In another aspect, the disclosure provides a method of administering venglustat, or a pharmaceutically acceptable salt thereof, to a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, wherein the venglustat or pharmaceutically acceptable salt thereof is administered in an effective amount to stabilize neurological function in the subject as assessed by the 9-HPT, the 25-FWT, and / or the FARS- neuro test.

[0070] The 9-HPT is a brief, standardized, quantitative test of upper extremity function, e.g. a test of dexterity. It is routinely used for testing motor function in conditions which present with progressive neurological decline (see, e.g., Mathiowetz et al., OTJR: Occup Particip Health (1985) 5(1):24— 38). As a measure of neurological decline, the 9-HPT test score is typically compared to baseline, with an increase relative to baseline indicating increased neurological impairment (decreased motor function). In embodiments of the present disclosure, the change in 9-HPT score from baseline is less than about 20%, e.g. less than about 16%, 12%, 10%, 8%, 6%, 4%, or 2%, over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the change in 9-HPT score from baseline is less than about 0% (i.e., negative) over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the change in 9-HPT score from baseline ranges from about -10% to about +10% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer), e.g. ranges from about -8% to about +8%, ranges from about -6% to about +6%, or ranges from about -4% to about +4%. In embodiments, the 9-HPT score does not change significantly over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the 9-HPT score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the 9-HPT score does not increase by more than about 10%, 8%, 6%, 4%, or 2% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

[0071] The 25-FWT (also known as T25-FW) is a quantitative mobility and leg function performance test. It is routinely used to test, e.g., gait speed and balance as measures of neurological function (see, e.g., pages 6-7 of “Multiple Sclerosis Functional Composite (MSFC) - Administration and Scoring Manual”, Ed. Fischer, Jak, Kniker, Rudick and Cutter; National Multiple Sclerosis Society, 2001). As a measure of neurological decline, the 25- FWT score is typically compared to baseline, with an increase relative to baseline indicating increased neurological impairment (decreased motor function). In embodiments of the present disclosure, the change in 25-FWT score from baseline is less than about 30%, e.g. less than about 25%, 20%, 15%, 10%, 8%, 6%, or 4%, over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the change in 25-FWT score from baseline ranges from about -20% to about +20% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer), e.g. ranges from about -15% to about +15%, ranges from about -10% to about +10%, or ranges from about -5% to about +5%. In embodiments, the 25-FWT score does not change significantly over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the 25-FWT score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the 25-FWT score does not increase by more than about 12%, 8%, 6%, or 4% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). The FARS-neuro test is a neurological component of the Friedreich Ataxia Rating Scale (FARS), a test directed to measuring the severity of neurologic dysfunction in patients with ataxias (see, e.g., Appendix E-l, part III of Subramony et al., Neurology (2005) 64(7): 1261- 1262). The FARS-neuro test combines bulbar, upper limb coordination, lower limb coordination, peripheral nervous system, and upright stability scores into a total neurologic examination score (0 to 117 points). As a measure of neurological decline, the FARS-neuro test score is typically compared to baseline, with an increase relative to baseline indicating increased neurological impairment. In embodiments of the present disclosure, the change in FARS-neuro score from baseline is less than about 5 points, e.g. less than about 0 points over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the change in FARS-neuro score from baseline ranges from about -10 points to about +10 points over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer), e.g. ranges from about -8 points to about +8 points, ranges from about -6 points to about +6 points, or ranges from about -4 points to about +4 points. In embodiments, the FARS-neuro score does not change over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the FARS-neuro score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the change in FARS-neuro score is less than 0 points (i.e., decreases) over a period of venglustat administration (e.g., up to about 12 weeks, up to about 24 weeks, up to about 36 weeks, up to about 52 weeks, or up to about 78 weeks).

[0072] In embodiments, the subject is female. In embodiments, the subject is male. In embodiments, the subject is treatment naive, e.g. the subject has not been subjected to any previous treatment (e.g., an investigative treatment) directed specifically at addressing GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis.

[0073] In embodiments, the subject suffers from GM1 gangliosidosis (e.g., late-onset GM1 gangliosidosis). In embodiments, the subject does not suffer from infantile GM1 gangliosidosis. In embodiments, the subject experienced onset of symptoms at an age ranging from 1 to 12 years old, e.g. ranging from 1 to 7 years old or from 2 to 6 years old, e.g. at age 1, 2, 3, 4, 5, 6, or 7. In embodiments, the subject was diagnosed as having GM1 gangliosidosis at an age ranging from 1 to 16 years old, e.g. ranging from 2 to 15 years old or ranging from 5 to 14 years old, e.g. at age 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In embodiments, administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age below about 35 years, e.g. below about 30 years, 25 years, 20 years, 15 years, 10 years, or 5 years. In embodiments, administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age ranging from 2 to 31 years old, e.g. at an age ranging from 2 to 19 years old or from 4 to 22 years old, e.g. at age 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22. In embodiments, the subject suffers from juvenile GM2 gangliosidosis. The subject may be an adult who experienced symptoms of, and / or received a diagnosis of, GM2 gangliosidosis as child or adolescent. In embodiments, the juvenile GM2 gangliosidosis is the Tay-Sachs variant. In embodiments, the juvenile GM2 gangliosidosis is the Sandhoff variant. In embodiments, the subject experienced onset of symptoms at an age ranging from 1 to 10 years old, e.g. ranging from 1 to 7 years old or from 1 to 5 years old, e.g. at age 1, 2, 3, 4, 5, 6, or 7. In embodiments, the subject was diagnosed as having GM2 gangliosidosis at an age ranging from 1 to 15 years old, e.g. ranging from 4 to 13 years old or from 4 to 10 years old, e.g. at age 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13. In embodiments, administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age below about 20 years, e.g. below about 16 years, 14 years, 12 years, 10 years, 8 years, 6 years, or 4 years. In embodiments, administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age ranging from 2 to 18 years old, e.g. at an age ranging from 4 to 16 years old or from 6 to 14 years old, e.g. at age 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0074] In embodiments, the subject suffers from sialidosis (e.g., Type I sialidosis). The subject may be an adult who experienced symptoms of, and / or received a diagnosis of, sialidosis as child or adolescent. In embodiments, the subject is female. In embodiments, the subject experienced onset of symptoms at an age ranging from 1 to 12 years old, e.g. at age 9. In embodiments, the subject was diagnosed as having sialidosis at an age ranging from 1 to 16 years old, e.g. at age 9. In embodiments, administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age below about 35 years, e.g. below about 30 years, or 25 years. In embodiments, administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age ranging from 2 to 25 years old, e.g. at age ranging from 16 to 24 years old, e.g. at age 23.

[0075] In embodiments, the subject suffers from sialidosis and the change in 9-HPT score from baseline is less than 0% (i.e., negative) over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the change in 9-HPT score from baseline is less than 0% (i.e., negative) over a period of at least 104 weeks. In embodiments, the change in 9-HPT score from baseline is less than (i.e., more negative than) -10%, e.g. less than -15%, -20%, or -25%, over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

[0076] In embodiments, the subject suffers from sialidosis and the change in FARS-neuro score from baseline is less than 0 points (i.e., decreases) over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer). In embodiments, the change in FARS-neuro score from baseline is less than 0 points over a period of at least 104 weeks. In embodiments, the change in FARS-neuro score from baseline is less than (i.e., more negative than) -5 points, e.g. less than -5, -10, -15, or -20 points, over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

[0077] In embodiments, the venglustat or pharmaceutically acceptable salt thereof is administered orally, e.g. in the form of a tablet or capsule. In embodiments, the venglustat or pharmaceutically acceptable salt thereof is administered once daily, e.g. at around the same time every day.

[0078] In embodiments, 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), for example in a dosage of about 4 mg, about 6 mg, about 12 mg or about 15 mg per day (calculated as the free base). In embodiments, the patient has a bodyweight 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 patient has a bodyweight of 15 kg to < 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 patient has a bodyweight 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 patient 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).

[0079] Forms of venglustat

[0080] The present disclosure contemplates various forms of venglustat including , e.g., venglustat in the form of a pharmaceutically acceptable salt.

[0081] In embodiments, the venglustat is in the form of venglustat free base, a pharmaceutically acceptable salt of venglustat, or a prodrug of venglustat as described herein. In one embodiment, the venglustat is in the form of venglustat malate salt, e.g., venglustat L-malate, optionally in crystalline form.

[0082] 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. 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.

[0083] Acids which can be used to prepare pharmaceutically acceptable salts of venglustat are those which can form non-toxic acid addition salts, e.g., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, malate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, and pamoate [i.e., 1,1'- methylene-bis-(2 -hydroxy-3 -naphthoate)] salts .

[0084] In one embodiment, the pharmaceutically acceptable salt is a succinate salt. In another embodiment, the pharmaceutically acceptable salt is a 2-hydroxysuccinate salt, e.g., an (S)-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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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 embodiments, the venglustat is in the form of a malate salt and is in crystalline Form A as described in WO 2014 / 152215 (see, e.g., claims 1-6). In other embodiments, the venglustat is in the form of a malate salt and is in crystalline Form B as described in WO 2014 / 152215 (see, e.g., claims 7- 12).

[0089] 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.

[0090] Pharmaceutical compositions

[0091] The venglustat, or pharmaceutically acceptable salt thereof, for use in accordance with present disclosure may be formulated as a pharmaceutical composition. The present disclosure thus provides a pharmaceutical composition (e.g., an oral pharmaceutical dosage form) comprising venglustat or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The composition may be specifically adapted for use in any of the methods disclosed herein.

[0092] In embodiments of the present methods, the venglustat or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition as described herein.

[0093] The pharmaceutically acceptable excipient can be any such excipient known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable excipient.

[0094] 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 comprises an amorphous solid dispersion comprising the venglustat with the pharmaceutically acceptable excipient.

[0095] 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 4 mg, or about 6 mg, or about 8 mg, or about 12 mg, or about 15 mg of venglustat (measured as the equivalent amount of free base).

[0096] 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. 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) 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.

[0097] 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.

[0098] 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%, or 0.01 to 10%, or 0.1 to 20%, or 0.1 to 15% or 0.1 to 10%, or 0.5 to 10%, or 0.5 to 5%, or 1 to 5%, or 2.5 to 5%, or 1 to 3%, or 0. 1 to 1% by weight. 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

[0099] 2-4%, or 2-3%, or about 3%; (c) from 2-15% by weight of disintegrant(s), e.g., 4-12%, or 6- 10%, or 7-9%, or about 8%; (d) from 0-12% by weight of binder(s), e.g., 2-10%, or 2-8%, or

[0100] 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).

[0101] In embodiments, the oral pharmaceutical composition is a pill, capsule, caplet, tablet, dragee, powder, granule, fdm, lozenge, or liquid. In embodiments, the oral pharmaceutical composition is a capsule or tablet, e.g., a tablet. In an embodiment, the oral pharmaceutical composition is a formulation as described in international patent application No.

[0102] PCT / IB2021 / 056673 (published as WO 2022 / 018695), the entire content of which is incorporated by reference herein.

[0103] In embodiments, the formulation is a capsule having the following composition:

[0104] In embodiments, the capsule contains 15 mg of venglustat (20. 16 mg of venglustat malate), the fdl mass of the capsule is 165 mg, and the formulation is packaged into a size #3 capsule shell.

[0105] In other embodiments, the formulation is a tablet having the following composition:

[0106] In embodiments, the tablet contains 15 mg of venglustat (20. 16 mg of venglustat malate), the flavor is apricot flavor, 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), the flavor is apricot flavor, and the weight of the tablet is 60 mg.

[0107] 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.

[0108] A pharmaceutical composition or dosage form of the present disclosure can include an agent and another carrier, e.g., compound or composition, inert or active, such as a detectable agent, label, adjuvant, diluent, binder, stabilizer, buffers, salts, lipophilic solvents, preservative, adjuvant, or the like. 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.

[0109] 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).

[0110] 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.

[0111] 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.

[0112] 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, com, 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.

[0113] 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.

[0114] Controlled release parenteral compositions can be in form of aqueous suspensions, microspheres, microcapsules, magnetic microspheres, oil solutions, oil suspensions, emulsions, or the active ingredient can be incorporated in biocompatible carrier(s), liposomes, nanoparticles, implants, or infusion devices. Materials for use in the preparation of microspheres and / or microcapsules include, but are not limited to, biodegradable / bioerodible polymers such as polyglactin, poly-(isobutyl cyanoacrylate), poly(2-hydroxyethyl-L- glutamine), and poly(lactic acid). Biocompatible carriers which can be used when formulating a controlled release parenteral formulation include carbohydrates such as dextrans, proteins such as albumin, lipoproteins, or antibodies. Materials for use in implants can be non-biodegradable, e.g., polydimethylsiloxane, or biodegradable such as, e.g., poly(caprolactone), poly(lactic acid), poly(glycolic acid), or poly(ortho esters).

[0115] Having been generally described herein, the following non-limiting examples are provided to further illustrate the disclosure.

[0116] EXAMPLES

[0117] Example 1A: Synthesis of (.S')-qiiinuclidin-3-yl 2-(2-(4-fluorophenyl)thiazol-4-yl)propan-2- ylcarbamate (venglustat)

[0118] To a stirred solution of 4-fluorothiobenzamide (8.94 g, 57.6 mmol) in ethanol (70 m ) was added ethyl 4-chloroacetoacetate (7.8 m , 58 mmol). The reaction was heated at reflux for 4 hours, treated with an addition aliquot of ethyl 4-chloroacetoacetate (1.0 mb, 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 mb) and aqueous NaHCCh (200 mb). The organic layer was combined with a backextract of the aqueous layer (ethyl acetate, 1 x 75 mb), dried (Na2SC>4), 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%).

[0119] To a stirred solution of ethyl 2-(2-(4-fluorophenyl)thiazol-4-yl)acetate (6.28 g, 23.7 mmol) in DMb (50 mb) 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 mb, 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 mb) and water (200 mb). The organic layer was washed with a second portion of water (1 x 200 mb), dried (Na2SC>4) 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%).

[0120] 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 THb / ethanol / water (45 mb) was added lithium hydroxide monohydrate (2.93 g, 69.8 mmol). The reaction was stirred overnight, concentrated, and redissolved in water (175 mb). The solution was washed with ether (1 x 100 mb), acidified by the addition of 1.0 N HC1 (80 mb) and extracted with ethyl acetate (2 x 70 mb). The combined extracts were dried (Na2SC>4) 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.

[0121] 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 NaHCCh (1 x 150 mL) and brine (1 x 100 mL), dried (Na2SC>4) 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 NaHCCh (150 mL). The organic layer was washed with water (1 x 150 mL), dried (Na2SC>4) 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%).1H NMR (400 MHz, CDCh) 5 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, CDCh) 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.

[0122] Example IB: Preparation of (.S')-Oiiinuclidin-3-yl (2-(2-(4-fluorophenyl)thiazol-4-yl)propan- 2-yl)carbamate (venglustat) in free base form

[0123] Step 1: Dimethylation with methyl iodide

[0124] Chemical Formula: C-|3H12FNO2S Chemical Formula: C15H16FNO2S

[0125] Exact Mass: 265.06 Exact Mass: 293.09

[0126] Molecular Weight: 265.30 Molecular Weight: 293.36

[0127] 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.

[0128] Step 2: Hydrolysis of the ethyl ester with LiOH monohydrate reflux, 16 h

[0129] Chemical Formula: CI5HI6FNO2S Chemical Formula: CI3HI2FNO2S Exact Mass: 293.09 Exact Mass: 265.06

[0130] Molecular Weight: 293.36 Molecular Weight: 265.30

[0131] 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 tetrahydrofiiran (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 anhydrous Na2SC>4, 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.

[0132] Step 3: Formation of hydroxamic acid with NH2OH.HCI

[0133] Chemical Formula: C13H12FNO2S Chemical Formula: Ci3H13FN2O2S Exact Mass: 265.06 Exact Mass: 280.07 Molecular Weight: 265.30 Molecular Weight: 280.32

[0134] The carboxylic acid (MW 265.3, 18.85 mmol, 5.0 g, 1.0 equiv.) was weighed and transferred to a 25 mb IN RB flask under nitrogen. THF (5.0 mb) 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.HCI; 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 mb) 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.HCI 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 mb). 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 Na2SC>4, 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. Step 3 continued: Conversion of hydroxamic acid to cyclic intermediate (not isolated)

[0135] Chemical Formula: Ci3H13FN2O2S Chemical Formula: C14H11FN2O3S Exact Mass: 280.07 Exact Mass: 306.05 Molecular Weight: 280.32 Molecular Weight: 306.31

[0136] 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 at room 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.

[0137] 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 CO2 and rearranged to the isocyanate (see below).

[0138] Chemical Formula: C14H11FN2O3S Chemical Formula: C13H11FN2OS Exact Mass: 306.05 Exact Mass: 262.06 Molecular Weight: 306.31 Molecular Weight: 262.30

[0139] Step 3 continued: Conversion of the isocyanate to the free base ,

[0140] Chemical Formula: C13H1 1FN2OS N2, 18 h Chemical Formula: C20H24FN3O2S Exact Mass: 262.06 Exact Mass: 389.16 Molecular Weight: 262.30 Molecular Weight: 389.49

[0141] The reaction mixture was cooled to 50-60°C and (S)-(+)-quinuclidinol (MW 127. 18, 28.28 mmol, 3.6 g, 1.5 equiv.) was added to the mixture as a solid in a single portion. The mixture was re-heated to reflux for 18 h. After 18 h, an aliquot was analyzed by HPLC and LC / MS which showed complete conversion of the isocyanate to the desired product. The reaction mixture was transferred to a separatory funnel and toluene (25 mL) was added. The mixture was washed with water (2 x 40 mL) and the water layers were separated. The combined water layers were re-extracted with toluene (30 mL) and the water layer was discarded. The combined toluene layers were extracted with 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 basified to pH 10-12 by the dropwise addition of 50% w / w aqueous NaOH. The desired free base precipitated out of solution as a dirty yellow gummy solid which could trap the stir bar. 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 Na2SC>4, fdtered 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.

[0142] Step 3 continued: Recrystallization of the crude free base

[0143] 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 fdtered 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. 'H NMR (400 MHz, CDCh) 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, CDCh) 5 166.38, 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.

[0144] Example 2: Preparation of crystalline forms of (.S')-Oiiinuclidin-3-yl (2-(2-(4- fluorophenyl)thiazol-4-yl)propan-2-yl)carbamate (venglustat) salts

[0145] Crystalline salts of (.S)-Quiniiclidin-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.

[0146] For example, the free base of (.S)-Quiniiclidin-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 fdtered. The fdtrate 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 dissolved in 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.

[0147] Crystal forms of other salts (e.g., acid addition salts with succinic acid or HC1) may be prepared in an analogous manner.

[0148] Example 3: Clinical study in patients with GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis

[0149] A clinical study was performed to assess the impact of venglustat in patients with GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis over a period of 2 years.

[0150] Patient demographics and study details

[0151] The demographics and baseline characteristics of the recruited patients are shown in Table 1 below:

[0152] Table 1: Demographics and baseline characteristics

[0153] Data are presented as mean ± standard deviation, or median [interquartile range], unless otherwise stated

[0154] * Three adult patients were enrolled in the trial: one aged 31 was diagnosed with GM1 gangliosidosis at age 14 (symptom onset at age 6); one aged 19 was diagnosed with GM1 gangliosidosis at age 15 (symptom onset at age 3); the other aged 23 was diagnosed with sialidosis (Type I) at age 9

[0155] Screening assessment was carried out before treatment initiation (Day -60 to Day -1), including assessing medical history and a confirmation of diagnosis (where appropriate) by genotyping, e.g. by HEXA I HEXB genotyping for Sandhoff and Tay-Sachs variants of GM2 gangliosidosis. Venglustat was administered during the primary treatment and analysis period. Dosages were set at 4 mg, 6 mg, 12 mg or 15 mg dosages once daily (calculated as free base), based on patient bodyweight - participants aged 18 years and older were administered the 15 mg daily dose irrespective of bodyweight:

[0156] Participants were scheduled for visits at week 0 (baseline), 12, 26, 52, 78 and 104, to carry out a physical examination (e.g., body weight, height and vital signs), as well as to take samples for haematology and urine biochemistry. ECG and ophthalmological examinations were scheduled at weeks 0, 26, 52, 78 and 104. 9-HPT, 25-FWT and FARS-neuro test were scheduled for all visits, and also for a visit at 12 weeks.

[0157] Results and conclusion

[0158] The stability over time of the 9-HPT score is shown in Figure 2 for patients with GM1 gangliosidosis and juvenile GM2 gangliosidosis. The stability over time of the 25-FWT score is shown in Figure 3 for patients with GM1 gangliosidosis and juvenile GM2 gangliosidosis. The stability over time of the FARS-neuro score is shown in Figure 4 for patients with GM1 gangliosidosis and juvenile GM2 gangliosidosis. The 9-HPT and FARS-neuro test scores for the patient with sialidosis are shown in Table 2 below (the sialidosis patient was wheelchairbound at baseline and hence was not assessed by 25-FWT):

[0159] Table 2: 9-HPT and FARS-neuro test scores for sialidosis patient

[0160] Of note, the change in the FARS-neuro score stays considerably below zero for the first 52 weeks of the study in the patients with GM1 gangliosidosis and juvenile GM2 gangliosidosis, while the score stays considerably below zero for the whole duration of the study in the patient with sialidosis.

[0161] Taken together, the results presented herein are consistent with a hypothesis that patients with GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, can experience a stabilization of neurologic function while being administered venglustat. It is to be understood that while the disclosure has been described in conjunction with the above embodiments, 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.

[0162] 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. 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

CLAIMS1. A method of stabilizing the 9-HPT, 25-FWT, and / or FARS-neuro test score in a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, the method comprising administering to the subject an effective amount of venglustat or a pharmaceutically acceptable salt thereof2. A method of administering venglustat, or a pharmaceutically acceptable salt thereof, to a human subject in need thereof suffering from GM1 gangliosidosis, juvenile GM2 gangliosidosis, or sialidosis, wherein the venglustat or pharmaceutically acceptable salt thereof is administered in an effective amount to stabilize the 9-HPT, 25-FWT, and / or FARS- neuro test score of the subject.

3. The method of claim 1 or claim 2, wherein the change in 9-HPT score from baseline is less than about 20%, or wherein the change in 9-HPT score from baseline ranges from about -10% to about +10% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

4. The method of claim 1 or claim 2, wherein the 9-HPT score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

5. The method of any one of claims 1 to 4, wherein the change in 25-FWT score from baseline is less than about 30% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer), or wherein the change in 25-FWT score from baseline ranges from about -20% to about +20% over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

6. The method of any one of claims 1 to 4, wherein the 25-FWT score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

7. The method of any one of claims 1 to 6, wherein the change in FARS-neuro score from baseline is less than about 5 points over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer), or wherein the change in FARS-neuro score from baseline ranges from about -10 points to about +10 points over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

8. The method of any one of claims 1 to 6, wherein the FARS-neuro score does not increase over a period of venglustat administration (e.g., up to about 12 weeks, 24 weeks, 36 weeks, 52 weeks, 104 weeks, or longer).

9. The method of any one of claims 1 to 8, wherein the subject suffers from GM1 gangliosidosis.

10. The method of claim 9, wherein administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age ranging from 2 to 19 years old.

11. The method of claim 9 or claim 10, wherein the subject experienced onset of symptoms at an age ranging from 1 to 7 years old, and / or wherein the subject was diagnosed as having GM1 gangliosidosis at an age ranging from 2 to 15 years old.

12. The method of any one of claims 1 to 8, wherein the subject suffers from juvenile GM2 gangliosidosis (e.g., wherein the juvenile GM2 gangliosidosis is the Tay-Sachs variant or the Sandhoff variant).

13. The method of claim 12, wherein administration of venglustat or a pharmaceutically acceptable salt thereof is initiated in the subject at an age ranging from 4 to 16 years old.

14. The method of claim 12 or claim 13, wherein the subject experienced onset of symptoms at an age ranging from 1 to 7 years old, and / or wherein the subject was diagnosed as having GM2 gangliosidosis at an age ranging from 4 to 13 years old.

15. The method of claim 1 or claim 2, wherein the subject suffers from sialidosis (e.g., Type I sialidosis).

16. The method of claim 15, wherein the change in 9-HPT score from baseline is less than 0% (i.e., negative) over a period of venglustat administration of at least 104 weeks.

17. The method of claim 15 or claim 16, wherein the change in FARS-neuro score from baseline is less than 0 points (i.e., decreases) over a period of venglustat administration of at least 104 weeks.

18. The method of any one of claims 1 to 17, wherein the venglustat or pharmaceutically acceptable salt thereof is administered orally, e.g. in the form of a tablet or capsule.

19. The method of any one of claims 1 to 18, wherein the venglustat or pharmaceutically acceptable salt thereof is administered once daily.

20. The method of any one of claims 1 to 19, wherein the venglustat or pharmaceutically acceptable salt thereof is administered in a dosage (calculated as the free base) of:(a) about 15 mg per day to a subject having a body weight of > 50 kg;(b) about 12 mg per day to a subject having a body weight of 30 kg to < 50 kg;(c) about 6 mg per day to a subject having a bodyweight of 15 kg to < 30 kg; or(d) about 4 mg per day to a subject having a bodyweight of 10 kg to < 15 kg.

21. The method of any one of claims 1 to 20, wherein the venglustat is in the form of venglustat free base, or a pharmaceutically acceptable salt of venglustat, optionally venglustat L-malate salt.

22. Venglustat, or a pharmaceutically acceptable salt thereof, for use in a method as claimed in any one of claims 1 to 21.

23. Use of venglustat, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method as claimed in any one of claims 1 to 21.

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