Arimoclomol for treating Gaucher disease

Abstract

The provision of arimoclomol for treating Gaucher's disease. The present invention relates to an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, and in particular to arimoclomol for use in methods for treating Gaucher disease (GD). This specification describes the results of a double-blind, randomized, placebo-controlled, Phase 2 dose-ranging study in patients with Gaucher disease (GD) types 1 and 3 who were not receiving enzyme and / or substrate replacement therapy.

Description

[Technical Field]

[0001] Technical Field The present invention relates to an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, and in particular to arimoclomol for use in an improved method of treating Gaucher disease (GD). [Background technology]

[0002] background Gaucher disease is an autosomal recessive lysosomal storage disorder (LSD) characterized by a deficiency of the enzyme glucocerebrosidase (GBA). The enzyme deficiency is caused by mutations in the gene GBA1, which leads to the accumulation of glucosylceramide (GlcCer) and its deacylated form, glucosylsphingosine (GlcSph). Glucosylsphingosine accumulates in the brain and is thought to be responsible for the neurological symptoms of Gaucher disease.

[0003] This disease is characterized by lysosomal dysfunction, cellular stress, and death caused by a significant decrease in enzyme activity. It is most often due to the L444P mutation, the homozygosity of which is strongly associated with the GD3 genotype (GD3). The L444P genotype has previously been demonstrated to respond to several heat shock protein (HSP) induction strategies.

[0004] Gaucher disease has traditionally been classified into three subtypes based on the presence or absence of primary central nervous system (CNS) involvement: GD1 type (GD1) with no neurological symptoms, GD2 type (GD2) with acute early neurological disease, and GD3 with a slower, chronic neuropathic disease.

[0005] Clinical onset of GD1 can occur at any age, but when symptoms begin in childhood, the phenotype is typically more severe and progresses more rapidly. The most frequent manifestations of the disease are splenomegaly, hepatomegaly, and bone disease, accompanied by anemia and thrombocytopenia (primarily due to hypersplenism). Signs and symptoms associated with hepatosplenomegaly can range from absence to abdominal distension, discomfort, or pain. Thrombocytopenia leads to an increased tendency for bleeding and bruising, and anemia can cause fatigue and growth failure with low body weight and reduced growth. Bone marrow infiltration by Gaucher cells leads to osteopenia, osteonecrosis, and osteosclerosis, sometimes resulting in acute onset of severe pain (bone spasms), chronic bone pain, and pathological fractures, which substantially impact patients' quality of life.

[0006] Gaucher disease type 3 is characterized as a milder chronic neurological disorder compared with GD2 (acute type). Symptoms begin later in childhood, with or without visceral and bone marrow involvement as seen in GD1. The earliest CNS involvement can be assessed by a detailed ophthalmologic examination, revealing abnormalities in horizontal saccade initiation, strabismus, and ocular palsy or paresis. Neurological progression is characterized by severe hypertonia, rigid arches (opisthotonus), ataxia, dysphagia, and seizures. Visceral disease in GD3 is often more severe than in GD1. Clinical scoring scales have been developed and validated to assess disease severity and the potential clinical benefit of treatment in both GD1 and GD3.

[0007] Two types of treatments are currently available for GD patients: enzyme replacement therapy (ERT), which uses recombinant GBA enzyme, and substrate reduction therapy (SRT), which acts by inhibiting GlcCer synthase, thereby reducing substrate production. Both types of treatment improve peripheral features of the disease but do not improve neurological symptoms and are therefore ineffective in treating neuropathic GD.

[0008] The accumulation of GlcCer and GlcSph in lysosomes occurs primarily in mononuclear macrophages, resulting in phagocytic macrophages called "Gaucher cells." In brain tissue from GD patients with neurological symptoms, neuronal loss and shrunken, atrophic neurons have been reported in the basal ganglia and nuclei of the midbrain, pons and medulla, cerebellum, dentate nucleus, and hypothalamus.

[0009] Chronic stimulation of the immune system occurs due to activated macrophages. Although there is considerable variability between patients, elevated levels of several interleukins ([IL]-1α, IL-1β, IL-1Ra, sIL-2R, IL-6, IL-8, IL-10, IL-18), tumor necrosis factor (TNF)-α, transforming growth factor-β, macrophage colony-stimulating factor, macrophage inflammatory protein-1 (MIP-1), and chemokine (CC motif) ligand 18 have been reported. The most important biomarker, chitotriosidase, is an enzyme produced in large amounts by macrophages and neutrophils. Histochemistry of bone marrow aspirates and spleen sections reveals these reservoir cells.

[0010] The HSR is an important homeostatic system that is induced under conditions of metabolic stress (e.g., protein misfolding and aggregation, nutrient deprivation, oxidative stress, or heat stress). Its main components are HSPs (especially HSP70), which have significant cytoprotective properties. Heat shock protein 70 acts as a molecular chaperone, assisting the folding of newly synthesized damaged proteins, preventing protein aggregation, and targeting severely damaged proteins for degradation. Notably, the cytoprotective effects of HSP70 include protection against lysosomal dysfunction, cell death, and demyelination in mouse studies. Arimoclomol is a safe and well-tolerated co-inducer of HSP70 expression that acts through activation of heat shock factor-1, a key regulator of HSP gene transcription. It is available for oral administration and exhibits the ability to cross the blood-brain barrier. Summary of the Invention

[0011] Abstract A double-blind, randomized, placebo-controlled, phase 2 dose-ranging study was conducted at seven centers in India in patients with Gaucher disease (GD) types 1 and 3 who were not receiving enzyme and / or substrate replacement therapy. A total of 39 patients were randomized 1:1:1:1 to receive placebo or 100 mg, 200 mg, or 400 mg of arimoclomol citrate (weight-adjusted) three times daily. The objective of the phase 2 study was to evaluate the response of three dose levels of arimoclomol on various clinical and disease-specific biomarkers over a 6-month treatment period. Overall, 37 patients were included in the analysis set (two patients were excluded because they had negative confirmatory GD genotypes), of which 21 were type 1 GD patients and 16 were type 3 GD patients.

[0012] The data presented herein demonstrate a dose-dependent effect of arimoclomol on certain disease-related secondary clinical endpoints, including liver and spleen size. Arimoclomol also demonstrated a relative decrease in serum chitotriosidase activity, and patients with baseline anemia demonstrated a time-dependent increase in hemoglobin at the highest dose.

[0013] The present disclosure provides an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method of treating Gaucher disease (GD), e.g., Gaucher disease (GD) type 1 (GD1) or GD3 (GD3), e.g., the active pharmaceutical ingredient is administered at 100 mg tid, e.g., 200 mg tid, e.g., 400 mg tid (equivalent to 300 mg / day, e.g., 600 mg / day, e.g., 1200 mg / day), or a corresponding weight-adjusted dose.

[0014] The present disclosure also provides an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in methods for reducing liver size / treating hepatomegaly, methods for reducing spleen size, treating splenomegaly, and methods for treating hepatosplenomegaly.

[0015] The present disclosure further provides an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating splenomegaly or hepatosplenomegaly associated with anemia and thrombocytopenia, e.g., a method for treating anemia and / or thrombocytopenia, e.g., a method for increasing hemoglobin.

[0016] The present disclosure further provides an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in methods for decreasing serum chitotriosidase activity and / or increasing glycosylsphingosine (lyso-Gb1). [Brief explanation of the drawings]

[0017] [Figure 1] Figure 1 shows the estimated plasma exposure of arimoclomol for patients in the three arimoclomol dose groups. Plasma exposure is estimated using population pharmacokinetic modeling. The AUC (area under the curve from time 0 to 8 hours) is shown for each patient in the three dose groups.

[0018] [Figure 2] Figure 2 shows the relative change in chitotriosidase activity from baseline versus placebo for each of the three arimoclomol dose groups.

[0019] [Figure 3] Figure 3 shows the relative change in liver size from baseline versus placebo for each of the three arimoclomol dose groups.

[0020] [Figure 4] Figure 4 shows the relative change in spleen size from baseline versus placebo for each of the three arimoclomol dose groups.

[0021] [Figure 5] FIG. 5 shows the mean hemoglobin concentration (g / L) over time for patients with anemia at baseline in the highest dose group (1200 mg / day).

[0022] [Figure 6] FIG. 6 shows the change from baseline in plasma glycosylsphingosine (lyso-Gb1) measured after 6 months. DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description definition In this context, the term "pharmaceutically acceptable derivatives" refers to salts that are not harmful to individuals, including pharmaceutically acceptable salts. Such salts include pharmaceutically acceptable base or acid addition salts, as well as pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. Pharmaceutically acceptable derivatives also include esters and prodrugs of compounds that can be biologically metabolized to active compounds, or other precursors, or crystalline forms of compounds.

[0024] The term "acid addition salt" is intended to include "pharmaceutically acceptable acid addition salts" which refer to salts that are not harmful to individuals. Acid addition salts include salts of inorganic acids and organic acids. Representative examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid, etc. Representative examples of suitable organic acids include formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, propionic acid, benzoic acid, cinnamic acid, citric acid, fumaric acid, glycolic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, picric acid, pyruvic acid, salicylic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, tartaric acid, ascorbic acid, pamoic acid, bimethylenesalicylic acid, ethanedisulfonic acid, gluconic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, EDTA, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 66, 2, (1977), which is incorporated herein by reference.

[0025] As used herein, the term "therapeutically effective amount" of a compound refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially halt the clinical symptoms of a given disease or disorder and its complications. An amount sufficient to achieve this is defined as a "therapeutically effective amount." The effective amount for each purpose will depend on the severity of the disease or injury and the weight and general condition of the individual. It will be understood that determining the appropriate dose can be accomplished using routine experimentation by constructing a matrix of values ​​and testing different points within the matrix, all of which is within the ordinary skill of a trained physician or veterinarian.

[0026] As used herein, the terms "treatment" and "treating" refer to the management and care of an individual with the goal of curing a condition, disease, or disorder. The term is intended to include the full range of treatments for a given condition from which the individual is suffering. The individual to be treated is preferably a mammal, particularly a human. However, treatment of animals such as mice, rats, dogs, cats, horses, cows, sheep, and pigs is also within the scope of this context. The individual to be treated can be of various ages.

[0027] Treatment method One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating Gaucher disease (GD).

[0028] An aspect of the present disclosure is also to provide a method of treating Gaucher disease (GD), comprising one or more steps of administering to an individual in need thereof an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof.

[0029] A further aspect of the present disclosure is to provide the use of an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof in the manufacture of a medicament for treating Gaucher disease (GD).

[0030] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating Gaucher disease (GD) type 1 (GD1) or GD3 (GD3).

[0031] In some embodiments, the active pharmaceutical ingredient is for use in a method for treating Gaucher disease (GD) type 1 (GD1) or GD3 (GD3), which is associated with deficiency of GBA enzyme activity below the lower limit of normal.

[0032] In some embodiments, the active pharmaceutical ingredient is for use in a method for treating Gaucher disease (GD) type 1 (GD1).

[0033] In some embodiments, the active pharmaceutical ingredient is for use in a method of treating symptoms of cerebral involvement, for example, Gaucher disease (GD) type 1 (GD1) associated with subclinical symptoms of cerebral involvement.

[0034] In some embodiments, the active pharmaceutical ingredient is for use in a method for treating Gaucher disease (GD) type 3 (GD3).

[0035] In some embodiments, the active pharmaceutical ingredient is for use in a method for treating symptoms of cerebral involvement, for example, Gaucher disease (GD) type 3 (GD3) with clinical symptoms of cerebral involvement.

[0036] In some embodiments, the active pharmaceutical ingredient is for use in a method for treating Gaucher disease (GD) type 3 (GD3) associated with at least one neurological symptom.

[0037] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for reducing a clinical composite score of Gaucher disease (GD) type 1.

[0038] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for reducing a clinical GD1 severity score.

[0039] In some embodiments, the active pharmaceutical ingredient is for use in a method for treating Gaucher disease (GD) in a patient aged 4 to 60 years.

[0040] In some embodiments, the active pharmaceutical ingredient is for use in a method for treating Gaucher disease (GD) in a patient aged 4 to 6 years, such as 6 to 8 years, such as 8 to 10 years, such as 10 to 12 years, such as 12 to 14 years, such as 14 to 16 years, such as 16 to 18 years.

[0041] In some embodiments, the active pharmaceutical ingredient is for use in a method for treating Gaucher disease (GD) in a patient weighing 10 kg or more.

[0042] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method of treating Gaucher disease (GD), wherein said active pharmaceutical ingredient is administered at 100 mg tid, for example 200 mg tid, for example 400 mg tid.

[0043] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method of treating Gaucher disease (GD), wherein the active pharmaceutical ingredient is administered at 300 mg / day, such as 600 mg / day, such as 1200 mg / day.

[0044] In some embodiments, the active pharmaceutical ingredient is administered at 100 mg tid, which corresponds to 300 mg / day ("low dose").

[0045] In some embodiments, the active pharmaceutical ingredient is administered at 200 mg tid, which corresponds to 600 mg / day (a "medium dose").

[0046] In some embodiments, the active pharmaceutical ingredient is administered at 400 mg tid, which corresponds to 1200 mg / day (the "high dose").

[0047] In some embodiments, the active pharmaceutical ingredient is administered in weight-adjusted doses, with low, medium, and high doses correlated to the patient's weight. The correlation between weight bands and doses is provided herein below.

[0048] An aspect of the present disclosure is also to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for reducing liver size.

[0049] In one embodiment, the method for reducing liver size is a method for reducing liver size in a patient with Gaucher disease.

[0050] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating hepatomegaly.

[0051] In one embodiment, the method for treating hepatomegaly is a method for treating hepatomegaly in a patient with Gaucher disease.

[0052] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for reducing spleen size.

[0053] In one embodiment, the method for reducing spleen size is a method for reducing spleen size in a patient with Gaucher disease.

[0054] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating splenomegaly.

[0055] In one embodiment, the method for treating splenomegaly is a method for treating splenomegaly in a patient with Gaucher disease.

[0056] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for reducing spleen and liver size.

[0057] In one embodiment, the method for reducing spleen and liver size is a method for reducing spleen and liver size in a patient with Gaucher disease.

[0058] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating hepatosplenomegaly.

[0059] In one embodiment, the method for treating hepatosplenomegaly is a method for treating hepatosplenomegaly in a patient with Gaucher disease.

[0060] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating splenomegaly associated with anemia and thrombocytopenia, or hepatosplenomegaly associated with anemia and thrombocytopenia.

[0061] In one embodiment, the method for treating splenomegaly accompanied by anemia and thrombocytopenia, or hepatosplenomegaly accompanied by anemia and thrombocytopenia, is a method for treating splenomegaly accompanied by anemia and thrombocytopenia, or hepatosplenomegaly accompanied by anemia and thrombocytopenia, in a patient with Gaucher disease.

[0062] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for treating anemia and / or thrombocytopenia.

[0063] In one embodiment, the method for treating anemia and / or thrombocytopenia is a method for treating anemia and / or thrombocytopenia in a patient with Gaucher disease.

[0064] In one embodiment, the Gaucher disease patient is anemic.

[0065] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for increasing hemoglobin.

[0066] In one embodiment, the method for increasing hemoglobin is a method for increasing hemoglobin in a patient with Gaucher disease.

[0067] In one embodiment, the method for increasing hemoglobin is a method for increasing hemoglobin in a patient with Gaucher disease who is anemic.

[0068] In one embodiment, the method for increasing hemoglobin is a method for increasing hemoglobin in an anemic patient with Gaucher disease.

[0069] In one embodiment, the treatment increases hemoglobin at a dose of 600 mg / day (200 mg tid) or greater, e.g., 600-900 mg / day (200-300 mg tid) or 900-1200 mg / day (300-400 mg tid), e.g., 600 mg / day (200 mg tid) or 1200 mg / day (400 mg tid).

[0070] In one embodiment, the treatment increases hemoglobin at a dose of 600 mg / day (200 mg tid) or greater, e.g., 600-900 mg / day (200-300 mg tid) or 900-1200 mg / day (300-400 mg tid), e.g., 600 mg / day (200 mg tid) or 1200 mg / day (400 mg tid), the doses being adjusted for body weight (see elsewhere herein).

[0071] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for reducing serum chitotriosidase activity.

[0072] In one embodiment, the method for reducing serum chitotriosidase activity is a method for reducing serum chitotriosidase activity in a patient with Gaucher disease.

[0073] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for increasing glucosylsphingosine (lyso-Gb1).

[0074] In one embodiment, the method for increasing glucosylsphingosine (lyso-Gb1) is a method for increasing glucosylsphingosine (lyso-Gb1) in a patient with Gaucher disease.

[0075] In one embodiment, the Gaucher disease (GD) is GD1 type (GD1) or GD3 type (GD3).

[0076] In one embodiment, the Gaucher disease (GD) is GD1 type (GD1).

[0077] In one embodiment, the Gaucher disease (GD) is GD3 type (GD3).

[0078] In one embodiment, the treatment reduces liver size in a dose-dependent manner.

[0079] In one embodiment, the treatment reduces spleen size in a dose-dependent manner.

[0080] In one embodiment, the treatment reduces chitotriosidase activity in a dose-dependent manner.

[0081] In one embodiment, the treatment increases hemoglobin in a time-dependent manner.

[0082] One aspect of the present disclosure is to provide an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for treating Gaucher disease (GD), wherein the maximum predicted AUC 0~8時間(high dose) had an AUC of 6 to 9 μg·h / mL after administration of a single dose. 0~8時間 is in the range of about 80.00% to about 125.00% of the

[0083] In some embodiments, the maximum predicted AUC 0~8時間 (high dose) has an AUC of 6 to 9 μg·h / mL, for example about 6 to 6.5, for example about 6.5 to 7, for example about 7 to 7.5, for example about 7.5 to 8, for example about 8 to 8.5, for example about 8.5 to 9 μg·h / mL after administration of a single dose 0~8時間 is in the range of about 80.00% to about 125.00% of the

[0084] In some embodiments, the maximum predicted AUC 0~8時間 (high dose) has an AUC of 6 to 9 μg·h / mL, for example about 6 to 6.5, for example about 6.5 to 7, for example about 7 to 7.5, for example about 7.5 to 8, for example about 8 to 8.5, for example about 8.5 to 9 μg·h / mL after administration of a single dose 0~8時間 and / or The single dose is 200 mg for patients weighing 30 kg to 50 kg or less, and / or The single dose is 300 mg for patients weighing 50 kg to 70 kg, and / or The single dose is 400 mg for patients weighing 70 kg or more.

[0085] In some embodiments, there is provided an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating Gaucher disease (GD), wherein after administration of 300 mg / day, an AUC 0~8時間、定常状態 has an AUC of approximately 1000 h·ng / mL 0~8時間、定常状態 is in the range of about 80.00% to about 125.00% of the

[0086] In some embodiments, the AUC 0~8時間、定常状態 After administration of 300 mg / day, the AUC0-8 of about 700 to 1300 h·ng / mL, e.g., about 800 to 1200 h·ng / mL, e.g., about 900 to 1100 h·ng / mL 時間、定常状態 is in the range of about 80.00% to about 125.00% of the

[0087] In some embodiments, there is provided an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating Gaucher disease (GD), wherein after administration of 600 mg / day, an AUC 0~8時間、定常状態 has an AUC of approximately 2000 h·ng / mL 0~8時間、定常状態 is in the range of about 80.00% to about 125.00% of the

[0088] In some embodiments, the AUC 0~8時間、定常状態 After administration of 600 mg / day, the AUC0-8 of about 1700 to 2300 h·ng / mL, e.g., about 1800 to 2200 h·ng / mL, e.g., about 1900 to 2100 h·ng / mL 時間、定常状態 is in the range of about 80.00% to about 125.00% of the

[0089] In some embodiments, there is provided an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof, for use in a method for treating Gaucher disease (GD), comprising: 0~8時間、定常状態 After a 1200 mg / day dose, the AUC 0~8時間、定常状態 is in the range of about 80.00% to about 125.00% of the

[0090] In some embodiments, the AUC 0~8時間、定常状態has an AUC of about 4500 to 5700 h·ng / mL, for example 4500 to 4600 h·ng / mL, for example 4600 to 4700 h·ng / mL, for example 4700 to 4800 h·ng / mL, for example 4800 to 4900 h·ng / mL, for example 4900 to 5000 h·ng / mL, for example 5000 to 5100 h·ng / mL, for example 5100 to 5200 h·ng / mL, for example 5200 to 5300 h·ng / mL, for example 5300 to 5400 h·ng / mL, for example 5400 to 5500 h·ng / mL, for example 5500 to 5600 h·ng / mL, for example 5600 to 5700 h·ng / mL 0~8時間、定常状態 is in the range of about 80.00% to about 125.00% of the

[0091] In one embodiment, the treatment is preventative, curative, or ameliorative. In one particular embodiment, the treatment is preventative. In another embodiment, the treatment is curative. In a further embodiment, the treatment is ameliorative.

[0092] In some embodiments, the individual has been previously treated for Gaucher disease with enzyme replacement therapy, substrate replacement therapy, blood transfusion and / or splenectomy, etc. In some embodiments, the individual has been previously treated with enzyme replacement therapy and / or substrate replacement therapy. In some embodiments, the individual has not been treated for Gaucher disease with enzyme replacement therapy, substrate replacement therapy, blood transfusion and / or splenectomy, etc. within 4 months, for example, within 3 months, for example, within 2 months, for example, within 1 month, prior to initiating treatment. In some embodiments, the individual has not been treated for enzyme replacement therapy and / or substrate replacement therapy within 4 months, for example, within 3 months, for example, within 2 months, for example, within 1 month, prior to initiating treatment. In some embodiments, the individual has not been treated for Gaucher disease with enzyme replacement therapy, substrate replacement therapy, blood transfusion and / or splenectomy, etc. In some embodiments, the individual has not been treated for Gaucher disease with enzyme replacement therapy and / or substrate replacement therapy.

[0093] The individual to be treated is preferably a mammal, particularly a human.However, the treatment of animals such as mice, rats, dogs, cats, horses, cows, sheep and pigs is also within the scope of the present disclosure.The individual to be treated can be of various ages, including infants, children, adolescents and adults.In a preferred embodiment, the individual used herein is a human being, male or female, of any age.

[0094] An "individual in need thereof" refers to an individual with a disease that can benefit from the present disclosure, the disease being Gaucher disease. A patient is considered an individual in need thereof, and a Gaucher disease patient is considered a patient in need thereof. The terms "individual" and "patient" may be used interchangeably herein.

[0095] Arimoclomol The present disclosure provides for this purpose an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof.

[0096] In some embodiments, the active pharmaceutical ingredient is a racemic form of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0097] In some embodiments, the active pharmaceutical ingredient is an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0098] In some embodiments, the active pharmaceutical ingredient is an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0099] In some embodiments, the active pharmaceutical ingredient is selected from the group consisting of (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride and (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0100] In some embodiments, the active pharmaceutical ingredient is selected from the group consisting of (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0101] In some embodiments, the active pharmaceutical ingredient is an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0102] In some embodiments, the active pharmaceutical ingredient is selected from the group consisting of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate.

[0103] In some embodiments, the active pharmaceutical ingredient is selected from the group consisting of (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, and (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate.

[0104] In some embodiments, the active pharmaceutical ingredient is (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate.

[0105] In some embodiments, the active pharmaceutical ingredient is arimoclomol.

[0106] In some embodiments, the active pharmaceutical ingredient is arimoclomol (free base), (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. Arimoclomol and its preparation are disclosed, for example, in WO 97 / 16439, WO 00 / 050403, and WO 01 / 79174. In some embodiments, arimoclomol is a citrate salt formulation of the free base, i.e., (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (also known as BRX-345). The free base of arimoclomol has the structure shown in Formula I: [ka]

[0107] Usage / Dosage The active pharmaceutical ingredient or compositions comprising such as defined herein are, in some embodiments, administered to an individual in need thereof in a pharmaceutically or therapeutically effective dose.

[0108] In some embodiments, the active pharmaceutical ingredient is administered once or several times daily, such as 1 to 3 times daily, such as 1 to 2 times daily, for example 2 to 3 times daily.

[0109] In some embodiments, the active pharmaceutical ingredient is administered daily, eg, once a day, eg, twice a day, eg, three times a day (tid).

[0110] In a preferred embodiment, the active pharmaceutical ingredient is administered three times a day (tid).

[0111] In some embodiments the active pharmaceutical ingredient is administered over a period of 1 week, such as more than 1 week, for example at or more than 2 weeks, such as at or more than 3 weeks, for example at or more than 4 weeks, such as at or more than 1 month, for example at or more than 2 months, such as at or more than 3 months, for example at or more than 4 months, such as at or more than 5 months, for example at or more than 6 months, such as at or more than 7 months, for example at or more than 8 months, such as at or more than 9 months, for example at or more than 9 months, such as at or more than 10 months, for example at or more than 11 months, or such as at or more than 1 year.

[0112] In some embodiments, the active pharmaceutical ingredient is administered for at least 6 months, hi some embodiments, the active pharmaceutical ingredient is administered for at least 9 months, such as at least 1 year, for example at least 18 months, for example at least 2 years, for example at least 30 months, for example at least 3 years, for example at least 4 years, for example at least 5 years, for example at least 6 years, for example at least 7 years, for example at least 8 years, for example at least 9 years, for example at least 10 years or more.

[0113] In some embodiments, the dose is calculated based on the free base of arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride).

[0114] In some embodiments, the dose is calculated based on arimoclomol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate).

[0115] Unless otherwise specified, the dosages of active pharmaceutical ingredients disclosed herein are given as the citrate salt, and the conversion scheme between the citrate salt and the free base is as follows:

[0116] [Table A]

[0117] In some embodiments, the active pharmaceutical ingredient is arimoclomol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate).

[0118] In some embodiments, the active pharmaceutical ingredient is administered at a dose of about 25 mg to about 800 mg, for example, about 100 mg to about 800 mg per dose. In some embodiments, the active pharmaceutical ingredient is administered at a dose of about 25 mg to about 50 mg, for example, about 50 mg to about 75 mg, for example, about 75 mg to about 100 mg, for example, about 100 mg to about 150 mg, for example, about 150 mg to about 200 mg, for example, about 200 mg to about 300 mg, for example, about 300 mg to about 400 mg, for example, about 400 mg to about 500 mg, for example, about 500 mg to about 600 mg, for example, about 600 mg to about 700 mg, for example, about 700 mg to about 800 mg per dose, preferably the active pharmaceutical ingredient is administered three times daily.

[0119] In some embodiments, the active pharmaceutical ingredient is administered at a dose of about 25 mg, such as about 50 mg, for example about 75 mg, for example about 100 mg, for example about 150 mg, such as about 200 mg, for example about 300 mg, such as about 400 mg, for example about 500 mg, such as about 600 mg, for example about 700 mg, for example about 800 mg, preferably the active pharmaceutical ingredient is administered three times daily.

[0120] In some embodiments, the active pharmaceutical ingredients are administered in a single dose of about 100 mg, e.g., about 200 mg, e.g., about 400 mg, preferably three times daily for the first active pharmaceutical ingredient. In some embodiments, the single dose is adjusted for body weight.

[0121] In some embodiments, the active pharmaceutical ingredient is administered at 100 mg tid, e.g., 200 mg tid, e.g., 400 mg tid. In some embodiments, the dose is adjusted for body weight.

[0122] In some embodiments, the active pharmaceutical ingredient is administered at a daily dose of about 100 mg / day to about 200 mg / day, such as about 200 mg / day to about 300 mg / day, for example, about 300 mg / day to about 400 mg / day, for example, about 400 mg / day to about 500 mg / day, for example, about 500 mg / day to about 600 mg / day, for example, about 700 mg / day to about 800 mg / day, for example, about 800 mg / day to about 900 mg / day, for example, about 900 mg / day to about 1000 mg / day, for example, about 1000 mg / day to about 1100 mg / day, for example, about 1100 mg / day to about 1200 mg / day.

[0123] In a preferred embodiment, the active pharmaceutical ingredient is administered in a daily dose of 300 mg / day, such as 600 mg / day, for example 1200 mg / day.

[0124] In preferred embodiments, the active pharmaceutical ingredient is administered orally, hi some embodiments, the active pharmaceutical ingredient is administered via a stomach tube.

[0125] In some embodiments, the active pharmaceutical ingredient is administered in a 25 mg, 50 mg, or 100 mg hard capsule.

[0126] In some embodiments, the active pharmaceutical ingredient is administered to a Gaucher disease patient weighing 10 kg or more.

[0127] In some embodiments, the active pharmaceutical ingredient is administered to a Gaucher patient in a dose based on the patient's weight.

[0128] In some embodiments, the active pharmaceutical ingredient is administered to a Gaucher patient in a weight-adjusted dose.

[0129] In some embodiments, the active pharmaceutical ingredient is administered at 100 mg tid, which corresponds to a dose of 300 mg / day. This is also referred to as a "low" dose.

[0130] In some embodiments, the active pharmaceutical ingredient is administered at 200 mg tid, which corresponds to a dose of 400 mg / day, also referred to as a "medium" dose.

[0131] In some embodiments, the active pharmaceutical ingredient is administered at 400 mg tid, which corresponds to a dose of 1200 mg / day, also referred to as the "high" dose.

[0132] In some embodiments, the active pharmaceutical ingredient is administered to a Gaucher disease patient weighing between 10 kg and 30 kg.

[0133] In some embodiments, the active pharmaceutical ingredient is administered at 25 mg tid ("low dose"), which corresponds to a dose of 75 mg / day to Gaucher patients weighing 10 kg to 30 kg or less.

[0134] In some embodiments, the active pharmaceutical ingredient is administered at 50 mg tid ("medium dose"), which corresponds to a dose of 150 mg / day in Gaucher patients weighing between 10 kg and up to 30 kg.

[0135] In some embodiments, the active pharmaceutical ingredient is administered at 100 mg tid ("high dose"), which corresponds to a dose of 300 mg / day in Gaucher patients weighing between 10 kg and up to 30 kg.

[0136] In some embodiments, the active pharmaceutical ingredient is administered to a Gaucher disease patient weighing 30 kg to 50 kg or less.

[0137] In some embodiments, the active pharmaceutical ingredient is administered at 50 mg tid ("low dose"), which corresponds to a dose of 150 mg / day in Gaucher patients weighing 30 kg to 50 kg or less.

[0138] In some embodiments, the active pharmaceutical ingredient is administered at 100 mg tid ("medium dose"), which corresponds to a dose of 300 mg / day in Gaucher patients weighing 30 kg to 50 kg or less.

[0139] In some embodiments, the active pharmaceutical ingredient is administered at 200 mg tid ("high dose"), which corresponds to a dose of 600 mg / day, to Gaucher patients weighing 30 kg to 50 kg or less.

[0140] In some embodiments, the active pharmaceutical ingredient is administered to a Gaucher disease patient weighing 50 kg to 70 kg or less.

[0141] In some embodiments, the active pharmaceutical ingredient is administered at 75 mg tid ("low dose"), which corresponds to a dose of 225 mg / day in Gaucher patients weighing 50 kg to 70 kg or less.

[0142] In some embodiments, the active pharmaceutical ingredient is administered at 150 mg tid ("medium dose"), which corresponds to a dose of 450 mg / day in Gaucher patients weighing 50 kg to 70 kg or less.

[0143] In some embodiments, the active pharmaceutical ingredient is administered at 300 mg tid ("high dose"), which corresponds to a dose of 900 mg / day, to Gaucher patients weighing 50 kg to 70 kg or less.

[0144] In some embodiments, the active pharmaceutical ingredient is administered to a Gaucher disease patient weighing 70 kg or more.

[0145] In some embodiments, the active pharmaceutical ingredient is administered at 100 mg tid ("low dose"), which corresponds to a dose of 300 mg / day in a Gaucher patient weighing 70 kg or more.

[0146] In some embodiments, the active pharmaceutical ingredient is administered at 200 mg tid ("medium dose"), which corresponds to a dose of 600 mg / day in Gaucher patients weighing 70 kg or more.

[0147] In some embodiments, the active pharmaceutical ingredient is administered at 400 mg tid ("high dose"), which corresponds to a dose of 1200 mg / day in a Gaucher patient weighing 70 kg or more.

[0148] In some embodiments, the active pharmaceutical ingredient is administered to a patient with Gaucher disease who is between the ages of 4 and 60.

[0149] In some embodiments, the active pharmaceutical ingredient is administered to a Gaucher patient at an age-based dose.

[0150] In some embodiments, the active pharmaceutical ingredient is administered at 100 mg tid, which corresponds to a dose of 300 mg / day in Gaucher patients over 18 years of age.

[0151] In some embodiments, the active pharmaceutical ingredient is administered at 200 mg tid, which corresponds to a dose of 600 mg / day to Gaucher patients over 18 years of age.

[0152] In some embodiments, the active pharmaceutical ingredient is administered at 400 mg tid, which corresponds to a dose of 1200 mg / day to Gaucher patients over 18 years of age.

[0153] In some embodiments, the active pharmaceutical ingredient is arimoclomol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate). In some embodiments, the dose of the active pharmaceutical ingredient is calculated based on arimoclomol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate).

[0154] formulation Although it is possible to administer active pharmaceutical ingredients as raw chemicals, in some embodiments, it is preferable to provide them in the form of pharmaceutical preparations. Thus, compositions comprising the active pharmaceutical ingredients defined herein, such as pharmaceutical compositions, i.e., pharmaceutically safe compositions, are also provided herein. In some embodiments, the compositions further comprise one or more pharmaceutically and / or physiologically acceptable diluents, carriers, and / or excipients.

[0155] In some embodiments, the composition is formulated for oral administration, e.g., in the form of a tablet or capsule, or as an oral powder, e.g., an oral powder suitable for suspension in a liquid, or e.g., as a suspension for oral administration.

[0156] Pharmaceutical compositions containing the active pharmaceutical ingredients of the present disclosure may be prepared by conventional techniques. [Example]

[0157] Example 1 - A multicenter, double-blind, randomized, placebo-controlled trial of arimoclomol in patients diagnosed with Gaucher disease type 1 or type 3 material and method Methods / Study Design This is a placebo-controlled, randomized, double-blind study evaluating the response of three dose levels of arimoclomol to various pharmacodynamic (PD) biomarkers in blood and cerebrospinal fluid (CSF) as indicators of enhanced glucocerebrosidase (GBA) enzyme activity on GD1 and GD3.

[0158] The purpose of this study was to evaluate whether arimoclomol can dose-dependently increase GBA enzyme activity in patients with GD. Changes in serum levels of well-established biomarkers related to GBA enzyme activity, as well as changes in hemoglobin and platelet counts, were assessed over a double-blind, 6-month period and compared with placebo. Because both GD1 and GD3 patients have signs of cerebral involvement (although nonclinical in GD1 patients), the same panel of biomarkers was assessed in the CSF of GD1 and GD3 patients.

[0159] Eligible GD1 and GD3 patients were randomized on a 1:1:1:1 basis into four groups to receive arimoclomol 300 mg / day, arimoclomol 600 mg / day, arimoclomol 1200 mg / day, or placebo treatment (administered three times daily [tid]).

[0160] Pediatric patients received a corresponding dose based on their body weight (kilograms). Adult patients randomized to the study before the protocol implementation date received a fixed dose, and adult patients randomized to the study after the protocol implementation date received an IMP dose based on their body weight. Patients were stratified according to GD type (type 1 or 3). Patients randomized to receive placebo were further randomized on a 1:1:1 basis to receive arimoclomol at 300 mg / day, 600 mg / day, or 1200 mg / day (in the absence of safety concerns) in the open-label extension phase of the study.

[0161] If an unacceptable adverse event (AE) occurred, as determined by the investigator, the patient received a reduced dose of the investigational product (IMP) until visit 3. Patients continued on the reduced dose for the remainder of the study.

[0162] All patients received a single dose of arimoclomol (100 mg single dose for the 300 mg / day treatment group, 200 mg single dose for the 600 mg / day treatment group, or 400 mg single dose for the 1200 mg / day treatment group, or the corresponding dose per kg for pediatric patients) before the protocol implementation date. Single-dose pharmacokinetics (PK) was performed at the corresponding dose per kg for all patients randomized after the protocol implementation date. PK evaluation was performed at the second postrandomization visit to confirm the suitability of the dose selected for this study (in terms of the target test drug (AUC0-8 - area under the curve from 0 to 8 hours [AUC] [AUC0-8])). After the single dose, blood samples for PK analysis were collected pre-dose and 0.5, 1, 2, 4, and 8 hours after administration. Patients randomized to the placebo group received the extension phase dose. The corresponding data were evaluated by an independent assessor to verify the AUC0-8. Patients then immediately began continuous administration of IMP according to randomization. IMP was administered three times daily (tid).

[0163] If the AUC was above target or an unexpected profile potentially affecting patient safety resulted in a dose reduction, patients received the reduced dose of IMP (blinded) on Visit 3. The dose level was recommended by an independent assessor. Additional blood samples for quantitative population pharmacokinetic analysis of arimoclomol were collected pre-dose and 0.5 hours post-dose on Visit 5 and pre-dose and 1.5 hours post-dose on Visit 7.

[0164] Cerebrospinal fluid samples for quantitative population pharmacokinetic analysis of arimoclomol were collected predose at Visit 5 and after the first daily dose at Visit 7. Results of the population pharmacokinetic analysis and PK / PD modeling were reported separately. Following the proof-of-concept phase, all patients were offered the opportunity to continue into the open-label extension phase, during which patients attended the site 1 month after the end of the blinded phase visit and every 6 months after the end of the blinded phase visit. During this open-label extension phase, patients who received arimoclomol during the proof-of-concept phase of the study continued on the same arimoclomol dose assigned to them, while patients who received placebo received arimoclomol 300 mg / day, 600 mg / day, or 1200 mg / day (adult patients) or the corresponding weight-adjusted dose (pediatric patients). All patients randomized after the protocol implementation date received an IMP dose based on weight.

[0165] Study population and patient numbers Male and female patients aged 4 to 60 years with a diagnosis of GD (either type 1 or type 3) comprised the study population. 40 patients were expected to be enrolled / randomized in the study.

[0166] Total randomized patient population: All patients who completed the screening procedures and were randomly assigned to a treatment group

[0167] Intent-to-treat (ITT) population: All randomized patients who received at least one dose of IMP and had valid serum chitotriosidase activity (primary endpoint) at baseline and any post-baseline visit

[0168] Per-protocol (PP) population: all randomized patients who received at least 80% of IMP during the treatment phase, had at least one chitotriosidase (CLS) measurement at baseline (visit 1 or 2) and at 6 months (visit 5), had plasma or serum chitotriosidase activity greater than 3 times the upper limit of normal applicable to local laboratory testing procedures (historical data were acceptable), and were confirmed as GD type 1 or 3 by genetic analysis at visit 4.

[0169] Blood / CSF population: All randomized patients who had blood and CSF measurements at visits 5 and 7 and correlated blood and CSF arimoclomol concentrations with chitotriosidase activity

[0170] All Patient Treatment Set: All patients who received at least one dose of IMP

[0171] Efficacy was analyzed using the ITT and PP populations, and safety was analyzed using the total patient treatment set (unless otherwise stated).

[0172] Diagnosis and Key Inclusion Criteria: The main inclusion criteria were: 1. The patient or their legal representative is able to read and understand the informed consent form. 2. The patient or their legal representative has signed the informed consent form. 3. Note that diagnostic local laboratory test results for either type 1 or type 3 GD with deficiency of GBA enzyme activity below the lower limit of normal were used in study selection. 4. For GD3, at least one neurological symptom 5. Age between 4 and 60 at the time of registration 6. Plasma or serum chitotriosidase activity greater than 3 times the upper limit of normal applicable to local laboratory testing procedures. Medical history data is within acceptable limits. 7. Have not received any treatment for GD or have not received any treatment for GD (investigational or licensed / approved such as enzyme replacement therapy or substrate reduction therapy, including procedures such as blood transfusion and splenectomy) within 4 months prior to study enrollment. 8. Ability to comply with protocol-specified procedures / assessments and scheduled visit dates (lumbar puncture was not performed if platelet count was less than 50,000 per microliter of circulating blood) 9. Ability to visit the study site repeatedly for assessment and follow-up (screening, baseline, 1, 3, 6, 7, 9, and 12 months, then every 6 months for the remainder of the extension portion) 10. All sexually active female patients of childbearing potential (postmenarche) must use highly effective contraception throughout the study and until 1 week after the last dose of IMP. Highly effective contraception includes combined (estrogen- and progestogen-containing) hormonal contraception (oral, intravaginal, or transdermal) associated with the suppression of ovulation, progestogen-only hormonal contraception (oral, injectable, or implantable) associated with the suppression of ovulation, intrauterine devices, intrauterine hormone-releasing systems, bilateral tubal occlusion, and partner vasectomy. All sexually active male patients with female partners of childbearing potential (postmenarche) must use condoms, with or without spermicide, in addition to the contraception used by their partners throughout the study and until 3 months after the last dose of IMP.

[0173] Exclusion criteria The main exclusion criteria were: 1. Liver transplant recipients or those planned for liver transplantation during the study period 2. Splenectomy within 4 months of study enrollment or planned during the study 3. Aspartate aminotransferase and / or alanine aminotransferase (central laboratory assessment) greater than 3 times the upper limit of normal for age and sex 4. Serum creatinine level greater than 1.5 times the upper limit of normal (central laboratory assessment) 5. Patients had received an IMP within 30 days prior to study enrollment (please note that according to enrollment criterion No. 7, an IMP for GD should not have been taken within the past 4 months prior to enrollment). 6. The patient is pregnant and / or breastfeeding. 7. If, in the opinion of the investigator, the patient has a clinical condition that does not meet the requirements of this protocol, e.g., a confirmed history of a serious adverse reaction to sedation or anesthesia (if sedation is required for lumbar puncture), severe uncontrolled epileptic seizures, and / or severe malnutrition Weight less than 8.10 kg

[0174] Test product, dosage and dosage form Arimoclomol was administered in 25 mg, 50 mg, and 100 mg hard capsules.

[0175] Reference therapy, dosage and dosage form Placebo: The placebo capsules were visually indistinguishable from the arimoclomol capsules in size and appearance. The placebo was provided in identical white hard capsules with identical capsule fill weights and was packaged and labeled as described for arimoclomol. The excipient composition, texture, appearance, solubility, odor, and flavor of the placebo were carefully matched to conceal the identity of the active capsule (arimoclomol).

[0176] IMPs (arimoclomol and placebo) were transported to the center at 2°C to 25°C and stored at ≤30°C.

[0177] Administration route IMP (arimoclomol or placebo) was administered orally three times daily. If needed, IMP was dispersed in 20 mL (i.e., 2 tablespoons) of liquid (apple juice, water, or milk) or 1 tablespoon of soft food (yogurt or applesauce). When dispersed, IMP was also administered via a gastric tube (if applicable). The tube was flushed with 5 mL of water for complete administration.

[0178] Dosage and Regimen For patients randomized prior to the implementation date of this protocol, the dose was administered in mg three times daily based on the patient's weight. (See Table 1 below.) For pediatric patients, the dose was administered according to weight as shown in Table 1 below. Adult patients (age 18 and older) received the fixed dose shown in Table 1 below.

[0179] [Table 1]

[0180] All patients, including adult patients randomized into the study after the implementation date of this protocol, received an IMP dose based on body weight, as shown in Table 2 below.

[0181] [Table 2]

[0182] Efficacy assessment Primary endpoint The primary efficacy endpoint of the study was the percent change in serum chitotriosidase activity (a marker of macrophage activation) from baseline to 6 months, with baseline defined as the mean of the pre-treatment visits (visits 1 and 2).

[0183] Secondary endpoints Measurement of growth and maturation Patients under 18 years of age: Changes in weight / height curves at 6 months and every other year until the end of the study Age at onset of puberty (Tanner stage II) in patients who had not reached puberty at the time of screening. Tanner stage (Tanner stages I to IV) at baseline and 6 months, and at least every 12 months thereafter until the end of the study. For adult patients aged 18 years and older, clinical efficacy outcomes were as follows: Change from baseline in body weight at 6 months and every 12 months thereafter until the end of the study

[0184] Imaging Endpoints Imaging efficacy endpoints consisted of changes in liver and spleen size (in centimeters) (assessed by ultrasound) at 6 months and every other year through the end of the study.

[0185] Clinical GD Severity Endpoints (All Patients): Gaucher disease type 1 disease severity scoring system (GD1-DS3) Modified Severity Scoring Tool (mSST)

[0186] Exploratory Endpoints Other exploratory endpoints included blood and CSF biomarker analysis and patient acceptability / preference for IMP.

[0187] Exploratory biomarker endpoints measured in blood included: Changes in plasma glucosylsphingosine (GlcSph) levels at 6 months and every 6 months until the end of the study * Changes in hemoglobin, ferritin, and platelet levels at 6 months and every 6 months until the end of the study * Changes in GBA enzyme activity (white blood cells) at 6 months and every 6 months until the end of the study * Changes in serum macrophage inflammatory protein-1b (MIP-1β, a cytokine for bone complications) at 6 months and every 6 months until the end of the study * * Change from baseline (Baseline defined as the mean of the pre-treatment visits (Visit 1 and Visit 2))

[0188] Exploratory biomarker endpoints measured in CSF included: Changes in glycoprotein nontransferase B at 6 and 12 months ** Changes in GlcSph levels at 6 and 12 months ** Changes in chitotriosidase activity (a marker of macrophage activation) at 6 and 12 months ** Changes in GBA enzyme activity levels at 6 and 12 months ** Changes in heat shock protein 70 levels at 6 and 12 months ** ** Change from the second visit to 6 or 12 months after the second visit

[0189] Pharmacokinetics Blood samples were collected after the first dose (visit day 2) at the following time points: 0.5, 1, 2, 4, and 8 hours post-dose. AUC0-8 after the first dose was used to assess whether exposure levels were acceptable. Additional blood samples for quantitative population PK analysis of arimoclomol plasma concentrations were collected pre-dose and 0.5 hours post-dose at visit day 5 and pre-dose and 1.5 hours post-dose at visit day 7.

[0190] Cerebrospinal fluid samples for quantitative population PK analysis of arimoclomol CSF concentrations were collected pre-dose at visit 5 and after the first daily dose at visit 7.

[0191] statistical methods The primary efficacy endpoint was analyzed using an analysis of covariance (ANCOVA) model for the ITT population. Logarithmic chitotriosidase activity was used for the analysis. The response variable in the ANCOVA model was logarithmic chitotriosidase activity at 6 months, and the independent variables included the randomized IMP dose (300 mg / day, 600 mg / day, 1200 mg / day, and 0 mg / day [placebo]), GD type, and logarithmic baseline chitotriosidase activity as continuous variables. An ancillary analysis was performed using the same model, but using the actual dose administered at Visit 3 after dosing adjustment based on potential PK assessments at Visit 2.

[0192] The following ANCOVA model was used to correlate the log of drug concentrations in blood and CSF with chitotriosidase activity in the blood / CSF population at 6 months: ANCOVA model for log of CSF drug concentration measured on visit 5, GD type, and log of baseline chitotriosidase activity as covariates. ANCOVA model for the log of blood drug concentration measured on visit 5, GD type, and the log of baseline chitotriosidase activity as covariates.

[0193] Secondary efficacy endpoints, including changes in weight and height, liver size, spleen size, and changes in biomarkers (blood and CSF) versus baseline (if appropriate), were analyzed using an ANCOVA model with treatment group (actual dose administered at Visit 3 after possible dosing adjustment based on PK assessment at Visit 2, or placebo) and corresponding baseline values ​​as covariates. For biomarker analysis, appropriate data transformations were performed, if necessary, prior to statistical analysis.

[0194] Descriptive statistics for age at pubertal onset and Tanner stage were provided by treatment group. No inferential analyses were performed.

[0195] Safety assessments included the following endpoints: incidence and severity of AEs (or treatment-emergent AEs [TEAEs]), C-SSRS, and mean and change from baseline, as well as laboratory safety laboratory and vital sign data considered clinically important. No formal statistical analysis of safety data was performed.

[0196] Arimoclomol plasma and CSF concentrations were summarized using descriptive statistics and by visit day and time point. The AUC0-8 after the first dose (visit day 2) was assessed using noncompartmental methods. Estimated AUC0-8 for each patient was listed.

[0197] The relationship between arimoclomol plasma and CSF concentrations and biomarkers was investigated. All plasma and CSF arimoclomol concentration and dosing data were combined with PK sampling date and time and used to create a population PK input file for use in population PK modeling analysis. Furthermore, the relationship between arimoclomol PK (plasma / CSF) and biomarkers was also investigated using a population PK / PD modeling approach.

[0198] Treatment period The proof-of-concept phase of the study was six months in duration. The open-label extension phase will continue until arimoclomol receives Marketing Authorisation (MA) in India or until analysis of data from the proof-of-concept phase of the study or information from the development programme, whichever comes first, no longer warrants its continuation.

[0199] Duration of patient participation in the study Randomization (Visit 2) occurred 7 to 35 days after screening (Visit 1). During the proof-of-concept, double-blind, placebo-controlled period of the study, patients visited the study at 1 month (Visit 3), 3 months (Visit 4), and 6 months (Visit 5 [end of blinded period]) after Visit 2. During the open-label extension phase of the study, patients visited the study at 1 month (Visit 6), 3 months (Visit 6.1), 6 months (Visit 7), and every 6 months thereafter until the end of the study. The total duration of patient participation in the study depended on the date of the MA in India or the availability of relevant data from the development program.

[0200] result Treatment Groups and Important Baseline Characteristics Thirty-nine subjects were randomized into the intention-to-treat (ITT) population, but two patients were excluded from the ITT set due to negative confirmatory GD genotype analysis (post-hoc). There were 31 children and 6 adults in the ITT analysis set.

[0201] The number of patients in each treatment group and their baseline characteristics are summarized in Table 3 below.

[0202] [Table 3]

[0203] Dose-dependent plasma exposure of arimoclomol Plasma exposure (AUC) was estimated for each patient using population PK modeling. A dose-dependent increase in plasma exposure was observed following administration of arimoclomol (see Figure 1).

[0204] Clinical findings Primary endpoint Chitotriosidase activity increased across all treatment groups, with a lower increase in the arimoclomol group compared to placebo. Although significance was not achieved (p=0.4), a relative decrease in chitotriosidase activity from baseline was observed in all dose groups compared to placebo (see Figure 2).

[0205] Secondary Clinical Endpoints Clinically significant dose-dependent reductions in liver size (dose trend effect p<0.05) and spleen size (dose trend analysis p<0.10) were observed compared to placebo (see Figures 3 and 4). The strong correlation between liver and spleen size and treatment (correlation coefficient: 0.53) confirms the consistency of effect.

[0206] Patients in the higher dose group who were anemic at baseline showed a time-dependent increase in hemoglobin (time trend analysis p<0.05) (see Figure 5).

[0207] A dose-dependent reduction in a validated clinical composite measure of Gaucher disease type 1 (the "Clinical GD1 Severity Score") was also observed, although this did not achieve statistical significance.

[0208] Other exploratory biomarkers: A trend towards a dose-dependent increase in glycosylsphingosine (lyso-Gb1) was observed (see Figure 6), but did not achieve statistical significance. In certain embodiments, for example, the following are provided: (Item 1) 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for treating Gaucher disease (GD). (Item 2) 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for treating Gaucher disease (GD), wherein the active pharmaceutical ingredient is administered at 100 mg tid, for example 200 mg tid, for example 400 mg tid. (Item 3) 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for treating Gaucher disease (GD), wherein the active pharmaceutical ingredient is administered at 300 mg / day, such as 600 mg / day, for example 1200 mg / day. (Item 4) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the Gaucher disease (GD) is GD1 type (GD1) or GD3 type (GD3). (Item 5) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the Gaucher disease (GD) is GD1 type (GD1) or GD3 type (GD3), which is accompanied by a deficiency of GBA enzyme activity below the lower limit of normal. (Item 6) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein said Gaucher disease (GD) is GD1 type (GD1). (Item 7) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the Gaucher disease (GD) is GD1 type (GD1) with signs of cerebral involvement, such as subclinical signs of cerebral involvement. (Item 8) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein said Gaucher disease (GD) is GD3 type (GD3). (Item 9) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the Gaucher disease (GD) is GD3 type with signs of cerebral involvement, such as clinical signs of cerebral involvement (GD3). (Item 10) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the Gaucher disease (GD) is GD3 type (GD3) with at least one neurological symptom. (Item 11) 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for treating hepatomegaly and / or reducing liver size. (Item 12) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the method is for treating hepatomegaly and / or reducing liver size in patients with Gaucher disease. (Item 13) 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for treating splenomegaly and / or reducing spleen size. (Item 14) Item 15. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the method is for treating splenomegaly and / or reducing the size of the spleen in patients with Gaucher disease. 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for treating hepatosplenomegaly and / or reducing the size of the liver and decreasing the size of the spleen. (Item 16) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the method is for treating hepatosplenomegaly and / or reducing liver size and reducing spleen size in Gaucher disease patients. (Item 17) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the splenomegaly is splenomegaly accompanied by anemia and thrombocytopenia. (Item 18) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the hepatosplenomegaly is hepatosplenomegaly accompanied by anemia and thrombocytopenia. (Item 19) 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof for use in a method for treating anemia and / or thrombocytopenia. (Item 20) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the method is for treating anemia and / or thrombocytopenia in Gaucher disease patients. (Item 21) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the Gaucher disease patient is anemic. (Item 22) 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof for use in a method for increasing hemoglobin. (Item 23) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the method is for increasing hemoglobin in Gaucher disease patients. (Item 24) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the method is for increasing hemoglobin and comprises administering the active pharmaceutical ingredient at a dose of 600 mg / day (200 mg tid) or more, for example, 600 to 900 mg / day (200 to 300 mg tid) or 900 to 1200 mg / day (300 to 400 mg tid). (Item 25) 10. The use of any one of the preceding items, wherein the method is for increasing hemoglobin and comprises administering the active pharmaceutical ingredient at a dose of 600 mg / day (200 mg tid) or 1200 mg / day (400 mg tid). Active pharmaceutical ingredient. (Item 26) 1. An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for reducing serum chitotriosidase activity. (Item 27) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the method is for reducing serum chitotriosidase activity in Gaucher disease patients. (Item 28) An active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, for use in a method for increasing glucosylsphingosine (lyso-Gb1). (Item 29) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the method is for increasing glucosylsphingosine (lyso-Gb1) in patients with Gaucher disease. (Item 30) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein said treatment reduces liver size in a dose-dependent manner. (Item 31) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein said treatment dose-dependently reduces spleen size. (Item 32) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein said treatment dose-dependently reduces chitotriosidase activity. (Item 33) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein said treatment increases hemoglobin in a time-dependent manner. (Item 34) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the individual has not been treated for Gaucher disease, such as by enzyme replacement therapy and / or substrate replacement therapy, within the past four months, or the individual to be treated has not previously been treated for Gaucher disease, such as by enzyme replacement therapy and / or substrate replacement therapy, e.g., the individual to be treated has never been treated with enzyme replacement therapy and / or substrate replacement therapy. (Item 35) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the treatment is preventative, curative or ameliorative. (Item 36) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is a racemate of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. (Item 37) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is an optically active stereoisomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. (Item 38) The active pharmaceutical ingredient is N-[2-hydroxy-3-(1-piperidinyl)-propoxy] 3. The active pharmaceutical ingredient for use according to any one of the preceding items, which is an enantiomer of [C1]-pyridine-1-oxide-3-carboximidoyl chloride. (Item 39) The active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, and (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride 10. The active pharmaceutical ingredient for use according to any one of the preceding items, selected from the group consisting of: (Item 40) The active pharmaceutical ingredient is (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride 10. The active pharmaceutical ingredient for use according to any one of the preceding items, selected from the group consisting of: (Item 41) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is an acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride. (Item 42) The active pharmaceutical ingredient is N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, and N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate 10. The active pharmaceutical ingredient for use according to any one of the preceding items, selected from the group consisting of: (Item 43) The active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, and (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate 10. The active pharmaceutical ingredient for use according to any one of the preceding items, selected from the group consisting of: (Item 44) The active pharmaceutical ingredient is (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate 10. The active pharmaceutical ingredient for use according to any one of the preceding items, selected from the group consisting of: (Item 45) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is arimoclomol. (Item 46) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is arimoclomol citrate. (Item 47) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered orally. (Item 48) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is formulated for oral administration, e.g. in the form of a tablet or capsule, or as an oral powder, e.g. an oral powder suitable for suspension in a liquid, or e.g. a suspension for oral administration. (Item 49) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered daily, such as once a day, such as twice a day, for example three times a day. (Item 50) 8. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered three times a day (tid). (Item 51) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered in a single dose of about 100 mg to about 400 mg, such as about 100 mg, 200 mg or 400 mg. (Item 52) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered at 100 mg tid, such as 200 mg tid, for example 400 mg tid. (Item 53) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered at 200 mg tid. (Item 54) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered at 100 mg tid. (Item 55) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered at 400 mg tid. (Item 56) The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered at a daily dose of from about 100 mg / day to about 200 mg / day, such as from about 200 mg / day to about 300 mg / day, for example from about 300 mg / day to about 400 mg / day, for example from about 400 mg / day to about 500 mg / day, such as from about 500 mg / day to about 600 mg / day, for example from about 700 mg / day to about 800 mg / day, such as from about 800 mg / day to about 900 mg / day, for example from about 900 mg / day to about 1000 mg / day, such as from about 1000 mg / day to about 1100 mg / day, for example from about 1100 mg / day to about 1200 mg / day. (Item 57) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered in a daily dose of 300 mg / day, such as 600 mg / day, for example 1200 mg / day. (Item 58) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered in a daily dose of 300 mg / day. (Item 59) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered in a daily dose of 600 mg / day. (Item 60) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered in a daily dose of 1200 mg / day. (Item 61) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered in 25 mg, 50 mg, and 100 mg hard capsules. (Item 62) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to a Gaucher disease patient weighing 10 kg or more. (Item 63) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients in a weight-adjusted dose. (Item 64) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to a Gaucher patient weighing between 10 kg and 30 kg. (Item 65) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing between 10 kg and up to 30 kg at a dose of 25 mg tid, which corresponds to a dose of 75 mg / day. (Item 66) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing between 10 kg and up to 30 kg at a dose of 50 mg tid, which corresponds to a dose of 150 mg / day. (Item 67) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing between 10 kg and up to 30 kg at a dose of 100 mg tid, which corresponds to a dose of 300 mg / day. (Item 68) The active pharmaceutical ingredient is administered to a patient with Gaucher disease weighing between 30 kg and 50 kg. , an active pharmaceutical ingredient for use according to any one of the preceding items. (Item 69) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing between 30 kg and 50 kg at a dose of 50 mg tid, which corresponds to a dose of 150 mg / day. (Item 70) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing between 30 kg and 50 kg at a dose of 100 mg tid, which corresponds to a dose of 300 mg / day. (Item 71) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing 30 kg to 50 kg at a dose of 200 mg tid, which corresponds to a dose of 600 mg / day. (Item 72) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to a Gaucher patient weighing between 50 kg and 70 kg. (Item 73) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing between 50 kg and 70 kg at a dose of 75 mg tid, which corresponds to a dose of 225 mg / day. (Item 74) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing between 50 kg and 70 kg at a dose of 150 mg tid, which corresponds to a dose of 450 mg / day. (Item 75) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients weighing between 50 kg and 70 kg at a dose of 300 mg tid, which corresponds to a dose of 900 mg / day. (Item 76) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to a Gaucher disease patient weighing 70 kg or more. (Item 77) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher disease patients weighing 70 kg or more at a dose of 100 mg tid, which corresponds to a dose of 300 mg / day. (Item 78) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher disease patients weighing 70 kg or more at a dose of 200 mg tid, which corresponds to a dose of 600 mg / day. (Item 79) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher disease patients weighing 70 kg or more at a dose of 400 mg tid, which corresponds to a dose of 1200 mg / day. (Item 80) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the Gaucher disease patient is between 4 and 60 years old. (Item 81) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the Gaucher patient is 4 to 6 years old, such as 6 to 8 years old, for example 8 to 10 years old, such as 10 to 12 years old, for example 12 to 14 years old, such as 14 to 16 years old, for example 16 to 18 years old. (Item 82) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher disease patients in an age-adjusted dose. (Item 83) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to a Gaucher disease patient over the age of 18. (Item 84) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients over 18 years of age at a dose of 100 mg tid, which corresponds to a dose of 300 mg / day. (Item 85) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients over 18 years of age at a dose of 200 mg tid, which corresponds to a dose of 600 mg / day. (Item 86) 10. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered to Gaucher patients over 18 years of age at a dose of 400 mg tid, which corresponds to a dose of 1200 mg / day. (Item 87) Maximum prediction AUC 0~8時間 (high dose) has an AUC of 6 to 9 μg·h / mL after administration of a single dose, e.g., about 6 to 6.5, about 6.5 to 7, about 7 to 7.5, about 7.5 to 8, about 8 to 8.5, or about 8.5 to 9 μg·h / mL after administration of a single dose 0~8時間 80.00% to about 125.00% of the active pharmaceutical ingredient for use according to any one of the preceding items. (Item 88) AUC 0~8時間、定常状態 However, after a 300 mg / day dose, the AUC 0~8時間、定常状態 80.00% to about 125.00% of about 700 to 1300 h·ng / mL, such as about 800 to 1200 h·ng / mL, for example about 80.00% to about 125.00% of about 900 to 1100 h·ng / mL after a dose of 300 mg / day. (Item 89) AUC 0~8時間、定常状態 However, after a 600 mg / day dose, the AUC 0~8時間、定常状態80.00% to about 125.00% of about 1700 to 2300 h·ng / mL, such as about 1800 to 2200 h·ng / mL, for example about 80.00% to about 125.00% of about 1900 to 2100 h·ng / mL after a 600 mg / day administration. (Item 90) AUC 0~8時間、定常状態 However, after a 1200 mg / day dose, the AUC 0~8時間、定常状態 and after a dose of 1200 mg / day, for example, about 4500 to 5700 h·ng / mL, for example, 4500 to 4600 h·ng / mL, for example, 4600 to 4700 h·ng / mL, for example, 4700 to 4800 h·ng / mL, for example, 4800 to 4900 h·ng / mL, for example, 4900 to 5000 h·ng / mL, for example, 5000 to 5100 h·ng / mL. 5. The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the saturation level is in the range of from about 80.00% to about 125.00% of 5100 to 5200 h·ng / mL, such as 5200 to 5300 h·ng / mL, for example 5300 to 5400 h·ng / mL, such as 5400 to 5500 h·ng / mL, for example 5500 to 5600 h·ng / mL, such as 5600 to 5700 h·ng / mL. (Item 91) the active pharmaceutical ingredient is refrigerated for 1 week, such as for more than 1 week, for example for 2 weeks or more than 2 weeks, for example for 3 weeks or more than 3 weeks, For example, 4 weeks or more than 4 weeks, for example 1 month or more than 1 month, for example 2 months or more than 2 months, for example 3 months or more than 3 months, for example 4 months or more than 4 months, for example 5 months or more than 5 months, for example 6 months or more than 6 months, Or, for example, the active pharmaceutical ingredient for use according to any one of the preceding items, administered for one year or for more than one year. (Item 92) The active pharmaceutical ingredient for use according to any one of the preceding items, wherein the active pharmaceutical ingredient is administered for at least 6 months, such as at least 9 months, for example at least 1 year, such as at least 18 months, for example at least 2 years, such as at least 3 years, for example at least 4 years, such as at least 5 years or more. (Item 93) A method for treating Gaucher disease (GD), comprising one or more steps of administering to an individual in need thereof an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and acid addition salts thereof.

Claims

1. A composition for use in a method for treating Gaucher disease (GD), said composition comprising an active pharmaceutical ingredient selected from N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers and acid addition salts thereof, wherein said GD is GD type 1 (GD1) or GD type 3 (GD3); the method is for use in treating hepatomegaly and / or reducing liver size in Gaucher disease patients; the method is for use in treating splenomegaly and / or reducing spleen size in Gaucher disease patients; The method is for use in treating hepatosplenomegaly and / or reducing liver size and reducing spleen size in Gaucher disease patients. The method is for use in treating anemia in Gaucher disease patients. the method is for use in increasing hemoglobin in Gaucher disease patients; the method is for use in reducing serum chitotriosidase activity in Gaucher disease patients; and / or The method is for use in increasing glycosylsphingosine (lyso-Gb1) in Gaucher disease patients.

2. The composition described in claim 1, wherein the Gaucher disease is GD1 or GD3 accompanied by signs of cerebral complications.

3. The composition described in claim 1 or 2, wherein the splenomegaly is splenomegaly accompanied by anemia and thrombocytopenia.

4. A composition described in any of claims 1 to 3, wherein the hepatosplenomegaly is hepatosplenomegaly accompanied by anemia and thrombocytopenia.

5. A composition described in any one of claims 1 to 4, wherein the Gaucher disease patient is anemic.

6. A composition described in any of claims 1 to 5, wherein the method for use in increasing hemoglobin comprises administering the active pharmaceutical ingredient at a dose of 600 mg / day (200 mg t.i.d.) or more, the dose being expressed as the citrate salt.

7. A composition described in any of claims 1 to 6, wherein the treatment dose-dependently reduces liver size, and / or the treatment dose-dependently reduces spleen size, and / or the treatment dose-dependently reduces chitotriosidase activity, and / or the treatment time-dependently increases hemoglobin.

8. A composition described in any of claims 1 to 7, wherein the individual has not been treated for Gaucher disease within the past four months or the individual to be treated has not previously been treated for Gaucher disease.

9. The active pharmaceutical ingredient is Racemic N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, Optically active stereoisomers of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, Enantiomers of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, Acid addition salt of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (-)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate, (Z)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (E)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, (Z)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate, and (E)-(S)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride maleate The composition according to any one of claims 1 to 8, selected from the group consisting of:

10. The active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride (arimoclomol free base), and (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol citrate) The composition according to any one of claims 1 to 9, selected from the group consisting of:

11. A composition according to any one of claims 1 to 10, wherein the active pharmaceutical ingredient is administered daily, preferably wherein the active pharmaceutical ingredient is administered three times a day (t.i.d.).

12. A composition described in any of claims 1 to 11, wherein the active pharmaceutical ingredient is administered in a dose of about 100 mg to about 400 mg per dose, the dose being expressed as the citrate salt.

13. The composition of any of claims 1 to 12, wherein the active pharmaceutical ingredient is administered at a daily dose of about 100 mg / day to about 200 mg / day, said dose being expressed as the citrate salt.

14. A composition according to any one of claims 1 to 13, wherein the active pharmaceutical ingredient is administered to a patient with Gaucher disease in a weight-adjusted or age-adjusted dose, the dose being expressed as the citrate salt.

15. The Gaucher disease patient is between 4 and 60 years old, and / or The composition according to any one of claims 1 to 14, wherein the Gaucher disease patient has a body weight of 10 kg or more.

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