Arimoclomol for the treatment of Niemann-Pick disease type C in patients with ER missense mutations

Abstract

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, for use in an improved method for the treatment of Niemann-Pick disease type C (NPC), in patients carrying an endoplasmic reticulum (ER)-type missense mutation in the NPC gene.

Description

[Technical field]

[0001] 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, for use in a method for the treatment of Niemann-Pick disease type C (NPC), in patients carrying an endoplasmic reticulum (ER)-type missense mutation in the NPC gene. [Background technology]

[0002] Lysosomal storage diseases (LSDs) are a group of rare disorders characterized by the accumulation of material within the lysosomal compartment and the resulting destabilization of the lysosomal compartment, with devastating effects for affected individuals.

[0003] Niemann-Pick disease type C (NPC) is a rare, progressive neurodegenerative disorder in which lysosomal function is impaired, leading to the accumulation of multiple lipid species in lysosomal and endosomal compartments. This lipid accumulation leads to neurodegeneration and visceral organ dysfunction. The clinical presentation and progression of NPC is heterogeneous, depends on the age at onset of neurological symptoms, and includes cognitive impairment as well as loss of motor function, swallowing, and speech. Affected individuals with early childhood onset of neurological symptoms generally have a more aggressive disease course than those with early-onset or late-onset disease.

[0004] A typical feature of NPC compared to other LSDs is that the stored storage material is highly complex and contains multiple different classes of lipids: in NPC, lysosomes accumulate cholesterol and multiple sphingolipids, including glycosphingolipids (GSLs) and sphingosine, and lysosomal calcium is reduced.

[0005] There is no specific cure for NPC, and mainly supportive care is available. These include medications to control seizures, abnormal limb postures, and tremors. Physical, speech, and occupational therapy are also used to assist with daily functioning. Attempts have been made to correct the cellular changes seen in NPC by performing liver or bone marrow transplants and using cholesterol-lowering drugs, but so far have not been effective in slowing neurological deterioration or disease progression.

[0006] Identifying the exact genetic and molecular mechanisms underlying NPC has been difficult. Autosomal recessive mutations in either the NPC1 (~95% of cases) or NPC2 (~5% of cases) genes, which encode lysosomal proteins essential for the intracellular transport and metabolism of lipids, have been identified as the primary genetic cause of NPC. However, numerous different classes of mutations have been identified in NPC1 and NPC2 in NPC patients, including missense mutations (70–80%) as well as splicing, frameshift, or premature stop mutations, collectively referred to herein as null-of-function mutations.

[0007] Several missense mutations are known to cause NPC. The I1061T mutation is the most commonly reported mutation, and in the homozygous state or in combination with a functional null allele, results in a clinical phenotype with late childhood or early juvenile onset and a "classic" increase in filipin staining in cultured fibroblasts. This mutation causes the NPC1 protein to become misfolded and retained in the endoplasmic reticulum (ER), where it is subsequently targeted for degradation. Several other mutations found in the NPC gene have been reported to result in similar phenotypes and are referred to herein as ER-type missense mutations.

[0008] Despite the identification of these mutations, it has been difficult to establish consistent genotype / phenotype relationships in NPC. Moreover, different genotypes / phenotypes respond differently to treatment; for example, treatment with miglustat has only a modest effect in slowing disease progression.

[0009] Therefore, there is an urgent need in the art for genotype / patient-specific therapeutic approaches for NPC. Summary of the Invention

[0010] The present invention addresses these needs by providing a targeted treatment for NPC patients, specifically the subset of NPC patients who have ER-type missense mutations.

[0011] The inventors have surprisingly found that NPC subjects carrying at least one ER-type missense mutation in at least one of the two alleles of the NPC gene respond strongly to treatment with arimoclomol.

[0012] 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, in a particular embodiment, arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate), for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject has an endoplasmic reticulum (ER)-type missense mutation in the NPC gene.

[0013] In some aspects of the disclosure, an active pharmaceutical ingredient that is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol) is provided in combination with a further active pharmaceutical ingredient that is N-butyl-deoxynojirimycin (miglustat) for use in a method for treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an ER-type missense mutation in the NPC gene.

[0014] In certain embodiments, ER-type missense mutations in the NPC gene result in the NPC protein being misfolded and retained in the endoplasmic reticulum (ER), where it is subsequently targeted for degradation.

[0015] In a specific embodiment, the NPC gene is NPC1 and the NPC protein is NPC1.

[0016] Also, an aspect of the present disclosure is to provide a method for predicting the responsiveness of a subject with Niemann-Pick disease type C (NPC) to treatment with arimoclomol, optionally in combination with miglustat, comprising: This method is a) determining whether a subject has an ER-type missense mutation in the NPC gene; b) predicting that the subject will respond to treatment with arimoclomol, optionally in combination with miglustat, if the subject is determined to have an ER-type missense mutation in the NPC gene; and Includes.

[0017] In some embodiments, a method is provided for identifying a subject with Niemann-Pick disease type C (NPC) that is likely to be responsive to treatment with arimoclomol, optionally in combination with miglustat, comprising: This method is a) determining whether a subject has an ER-type missense mutation in the NPC gene; b) if the subject is determined to have an ER-type missense mutation in the NPC gene, identifying the subject as likely to respond to treatment with arimoclomol, optionally in combination with miglustat; Includes. [Brief description of the drawings]

[0018] [Figure 1A]Figure 1 shows the observed change in the 5-domain NPCCSS score compared to baseline at 12 months after treatment with arimoclomol or placebo. Observed change in the 5-domain NPCCSS score compared to baseline for the entire population of subjects in the study. The solid lines represent least squares mean estimates ± standard error based on data obtained while the subjects were receiving the study treatment. Mixed models for repeated measures included main effects for baseline and stratum, respectively, and an interaction between treatment and visit. Changes from baseline and absolute estimates represent the mean values ​​across subjects at baseline. Numbers of subjects are presented by time point. Data are further described in Example 1. [Figure 1B] Figure 1 shows the observed change in 5-domain NPCCSS scores compared to baseline at 12 months after treatment with arimoclomol or placebo. Observed change in 5-domain NPCCSS scores compared to baseline for subjects who were > 4 years old. Solid lines represent least squares mean estimates ± standard error based on data obtained while subjects were receiving study treatment. Mixed models for repeated measures included main effects for baseline and stratum, respectively, and an interaction between treatment and visit. Change from baseline and absolute estimates represent the mean across subjects at baseline. Numbers of subjects are presented by time point. Data are further described in Example 1. [Figure 1C] Figure 1 shows the observed change in the 5-domain NPCCSS score compared to baseline at 12 months after treatment with arimoclomol or placebo. Observed change in the 5-domain NPCCSS score compared to baseline for subjects who were also treated with miglustat. The solid line represents the least squares mean estimate ± standard error based on data obtained while the subjects were receiving the study treatment. Mixed models for repeated measures included main effects for baseline and stratum, respectively, and an interaction between treatment and visit. Change from baseline and absolute estimates represent the mean value across subjects at baseline. Numbers of subjects are presented by time point. Data are further described in Example 1. [Figure 1D]Figure 1 shows the observed change in the 5-domain NPCCSS score compared to baseline at 12 months after treatment with arimoclomol or placebo. Observed change in the 5-domain NPCCSS score compared to baseline for subjects with either missense / missense or missense / functional null NPC genotypes (excluding patients with double functional null mutations). Solid lines represent least squares mean estimates ± standard error based on data obtained while subjects were receiving study treatment. Mixed models for repeated measures included main effects for baseline and stratum, respectively, and an interaction between treatment and visit. Change from baseline and absolute estimates represent the mean across subjects at baseline. Numbers of subjects are presented by time point. Data are further described in Example 1. [Figure 1E] Figure 1 shows the observed change in 5-domain NPCCSS scores compared to baseline at 12 months after treatment with arimoclomol or placebo. Patient-level change in 5-domain NPCCSS scores from baseline to last available data for all subjects in this study. Data are further described in Example 1. [Figure 2A] Figure 1 shows graphs of biomarker analysis in subjects receiving arimoclomol or placebo. Changes in HSP70 in PBMCs from months 0 to 12 in patients treated with arimoclomol. Data are further described in Example 1. [Figure 2B] Figure 1 shows graphs of biomarker analysis in subjects receiving arimoclomol or placebo. Change in non-esterified cholesterol levels at 12 months. Error bars indicate standard error. Data are further described in Example 1. [Figure 2C] 1 shows graphs of biomarker analysis in subjects receiving arimoclomol or placebo. Change in serum cholestanetriol levels at 12 months (difference between groups: p=0.225). Error bars indicate standard error. Data are further described in Example 1. [Diagram 3]Figure 1 shows relative HSP1A1 expression in NPC fibroblasts with ER genotype treated with various concentrations of arimoclomol. HSP1A1 expression levels are quantified on days 2 and 5. Data are further described in Example 2. [Figure 4] Quantification of NPC1 protein upon treatment of NPC patient-derived fibroblast cell lines with arimoclomol (50-400 μM arimoclomol for 5 days). NPC1 protein was quantified by Western blotting compared to tubulin (GM18453 & GM18420) or Ponceau staining (all other cell lines). Values ​​represent the mean + standard deviation (SD) of 3-5 independent experiments, as indicated. Statistical analysis was performed by two-way ANOVA with Dunnett's multiple comparison test (p: *<0.05, **<0.01, ***<0.001, ****<0.0001). Data are further described in Example 2. [Figure 5A] Western blotting of extracts from NPC fibroblast cell lines carrying P1007A and a functional null allele (GM18420), or homozygous I1061T NPC1 (GM18453) are shown. PNGase cleaves all glycans from the NPC1 protein, regardless of maturation state, and is included as a control. EndoH-sensitive immature NPC1 is seen in untreated GM18453 extracts. Data are further described in Example 2. [Figure 5B] Quantification of EndoH-resistant NPC1. Shown as arimoclomol-treated cells versus untreated cells. Cells were treated with 400 μM arimoclomol for 5 days. Mean of three independent experiments, mean ± SD. Pairwise t-test (p: *<0.05). Data are further described in Example 2. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] definition The term "pharmaceutically acceptable derivatives" in this context includes pharmaceutically acceptable salts, which refer to salts that are not harmful to the subject. 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 further include esters and prodrugs of a compound, or other precursors that can be metabolized to a biologically active compound, or crystalline forms of a compound.

[0020] The term "acid addition salt" is intended to include "pharmaceutical acceptable acid addition salts" which refer to salts that are not harmful to the subject. 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, and the like. 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, bismethylenesalicylic 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 pharma- ceutically acceptable inorganic or organic acid addition salts include those listed in J. Pharm. Sci. 66, 2, (1977), which is incorporated herein by reference.

[0021] The term "therapeutically effective amount" of a compound as used herein refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially arrest 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 amount effective for each purpose will depend on the severity of the disease or injury, as well as the weight and general condition of the subject. It will be understood that the determination of the appropriate dosage can be achieved using routine experimental methods by constructing a matrix of values ​​and testing different points within the matrix, all of which are within the ordinary skill of a trained physician or veterinarian.

[0022] For any compound, the therapeutically effective amount can be estimated in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine the appropriate concentration range and route of administration. Such information can be used to determine the dose and route useful for administration to humans. Therapeutic / prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD50 / ED50. The dose can vary within this range depending on the dosage form used and the sensitivity of the subject.

[0023] The term "subject" includes any organism having or at risk of developing NPC. In some embodiments, the term "subject" refers to a mammal having or at risk of developing NPC. In some embodiments, the term "subject" refers to a human having or at risk of developing NPC. The term "patient" is meant to be synonymous and can be used interchangeably with "subject" unless expressly indicated otherwise.

[0024] Niemann-Pick disease type C (NPC) is a rare, progressive genetic disorder characterized by the body's inability to transport cholesterol and other fatty substances (lipids) into cells, which leads to the abnormal accumulation of these substances in various tissues of the body, including brain tissue.

[0025] The terms "treatment" and "treating" as used herein refer to the management and care of a subject for the purpose of combating a condition, disease or disorder. The term is intended to include all therapies for a given condition suffered by the subject. The subject to be treated is preferably a mammal, in particular a human. However, treatment of animals such as mice, rats, dogs, cats, horses, cows, sheep and pigs is also within the scope of the present invention. The subject to be treated can be of various ages.

[0026] References to "treating" or "treatment" should be understood to include the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a condition, disorder, or condition includes (1) delaying the appearance of clinical symptoms of the condition, disorder, or condition that develop in a human who may be afflicted with or predisposed to the condition, disorder, or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the condition, disorder, or condition, (2) inhibiting the condition, disorder, or condition, i.e., arresting, alleviating, or delaying (in the case of maintenance therapy) the onset of the disease or its recurrence, or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the condition, disorder, or condition, or at least one clinical or subclinical symptom thereof.

[0027] The term "early treatment initiation" refers to initiating administration of arimoclomol as early as possible in the course of NPC in a subject, for example, as soon as the subject is diagnosed with NPC or during the period in which the subject exhibits a 5-domain NPCCSS, 17-domain NPCCSS, and / or ASIS score below some predetermined cutoff value.

[0028] As used herein, the terms "preventing," "prevent," or "protecting from" refer to reducing or eliminating the onset of symptoms or complications of such a disease, condition, or disorder.

[0029] As used herein, the terms "administer", "administering", "administration", and the like refer to methods that can be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed., Pergamon, and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0030] Additionally, arimoclomol can be co-administered with other therapeutic agents. The terms "co-administered," "administered in conjunction with," "administered close in time," and their grammatical equivalents, as used herein, are meant to encompass administration of two or more therapeutic agents to a single subject and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, arimoclomol is co-administered with other agents. These terms encompass administration of two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. They include co-administration in separate compositions, administration at different times in separate compositions, and / or administration as a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered as a single composition. In some embodiments, the compounds described herein and the other agent(s) are mixed as a composition.

[0031] The particular method and regimen of administration will be selected by the attending clinician considering the particulars of the case (e.g., subject, disease, pathology involved, particular treatment). Treatment can include daily or multiple day or less than daily (e.g., weekly or monthly) doses over a period ranging from several days to several months or even years. However, one of skill in the art will readily recognize appropriate and / or equivalent doses by consulting the dosages of compositions approved for treating NPC using arimoclomol as a guide.

[0032] The compounds taught herein or corresponding pharmaceutical compositions can be administered to a patient in various forms depending on the selected route of administration, as will be appreciated by those skilled in the art. The compounds of the present teachings can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration, and the pharmaceutical compositions can be formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal and topical administration methods. Parenteral administration can be by continuous infusion over a selected period of time.

[0033] The pharmaceutical composition of the present application is formulated to be compatible with its intended route of administration.In some embodiments, the composition is formulated according to conventional procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0034] The term "null-of-function mutation" refers to a mutation in a gene that results in a truncated, defective protein produced from an allele that has a null-of-function mutation. As used herein, a null-of-function mutation is either a frameshift mutation, an aberrant splicing mutation, or a premature stop codon mutation.

[0035] The term "frameshift mutation" refers to either a deletion or insertion of any number of nucleotides in an allele of a gene in the genome of a subject, where the number of nucleotides is not divisible by three, thereby altering the reading frame of the transcript produced from the mutated allele compared to the transcript produced from the wild-type allele.

[0036] The term "aberrant splicing variant" refers to a variant that alters the splicing activity of a transcript that contains the variant compared to a transcript having a wild-type sequence.

[0037] The term "premature stop mutation" refers to a single base mutation that results in the generation of a premature stop codon, resulting in the production of a truncated protein product compared to the wild-type sequence.

[0038] The term "missense mutation" refers to a substitution of one or more bases in a gene that results in a single amino acid change in the protein produced by a gene carrying the mutation compared to the protein produced by the wild-type gene.

[0039] The term "ER-type missense mutation" refers to one or more base substitutions in a gene that results in a single amino acid change in the protein produced by the gene with the mutation compared to the protein produced by the wild-type gene. In certain embodiments, ER-type missense mutations in NPC genes (e.g., NPC1 or NPC2) result in the NPC protein (e.g., NPC1 or NPC2) being misfolded, retained in the endoplasmic reticulum (ER), and / or subsequently targeted for degradation. Examples of ER-type missense mutations and methods for classifying mutations as ER-type missense mutations are further provided in Shammas et al., 2019 and Wang et al., 2020 (ER-type missense mutations are referred to as "ER-blocked" and "Class II" in Shammas et al., 2019 and Wang et al., 2020, respectively).

[0040] The term "NPC1" refers to the gene encoding Niemann-Pick C protein 1, also known in the art as NPC intracellular cholesterol transporter 1. The term "NPC1" refers to the protein product of the NPC1 gene.

[0041] The term "NPC2" refers to the gene encoding Niemann-Pick C protein 2, also known in the art as NPC intracellular cholesterol transporter 1. The term "NPC2" refers to the protein product of the NPC2 gene.

[0042] The term "genotype" refers to the mutation status of both alleles of a particular locus in a subject. As known to those skilled in the art, genotypes are described herein by a description of the mutation in the first allele (e.g., missense, functional null, specific mutation description), followed by a " / ", followed by a description of the mutation in the second allele (e.g., missense, functional null, specific mutation description).

[0043] The term "NPC1 genotype" refers to a subject's genotype at the NPC1 locus.

[0044] The term "NPC2 genotype" refers to a subject's genotype at the NPC2 locus.

[0045] The term "compound heterozygote" refers to a subject that has two different mutation alleles at a particular locus (e.g., an NPC locus such as the NPC1 locus or the NPC2 locus). For example, a subject with an "ER missense" / "ER missense" NPC genotype is considered a compound heterozygote if the subject has a first ER missense mutation in a first NPC allele and a second ER missense mutation in a second NPC allele, and the first and second missense mutations are different.

[0046] As will be appreciated by those of skill in the art, in this disclosure, mutations at both the genomic and protein levels are labeled according to the 2016 standards of Human Genome Variation Society (HGVS) and Human genome Organization (HUGO) nomenclature. DNA mutations are numbered relative to the NPC1 cDNA. The single letter amino acid code is used throughout, with frameshift mutations labeled with "fs" after the first affected amino acid, splice mutations indicated with "sp" after the last predicted correctly translated amino acid, and "splice" mutations indicated with "sp" after the last predicted correctly translated amino acid. * " indicates a stop codon.

[0047] The variant nomenclature used herein with respect to nucleotide positions refers to positions within the NPC1 cDNA sequence as set forth in National Library of Medicine entry NM_000271.5:

[0048] The variant nomenclature used herein with respect to amino acid positions refers to positions within the NPC1 protein sequence as set forth in National Library of Medicine entry NP_000262.2:

[0049] The terms "approximately" and "about" referred to herein are synonymous. In some embodiments, "approximately" and "about" refer to ±5%, ±4.5%, ±4%, ±3.5%, ±3%, ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.09%, ±0.08%, ±0.07%, ±0.06%, ±0.05%, ±0.04%, ±0.03%, ±0.02%, or ±0.01% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±1% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±0.5% of the recited amount, value, or duration. In some embodiments, "approximately" and "about" refer to ±0.1% of the recited amount, value, or duration.

[0050] Treatment method Arimoclomol is an orally bioavailable small molecule that crosses the blood-brain barrier, as evidenced by its presence in the cerebrospinal fluid of treated amyotrophic lateral sclerosis patients. The present disclosure relates, at least in part, to methods of treating Niemann-Pick disease type C (NPC) in specific clinical subsets of subjects by administering arimoclomol alone or in combination with miglustat.

[0051] It will be understood that references herein to arimoclomol can include both the free base form ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride), including acid addition salts thereof, and the citrate form ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate). It is the citrate form that is currently being studied in clinical trials.

[0052] One aspect of 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 for treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an endoplasmic reticulum (ER)-type missense mutation in the NPC gene.

[0053] In some aspects of the disclosure, there is provided an active pharmaceutical ingredient that is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, and acid addition salts thereof, for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an endoplasmic reticulum (ER)-type missense mutation in the NPC gene.

[0054] In some aspects of the disclosure, there is provided an active pharmaceutical ingredient that is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol) for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an endoplasmic reticulum (ER)-type missense mutation in the NPC gene.

[0055] An aspect of the present disclosure also provides a method for treating or preventing Niemann-Pick disease type C (NPC) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount 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, wherein the subject has an ER-type missense mutation in the NPC gene.

[0056] In some aspects of the disclosure, there is provided 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, for the manufacture of a medicament for the treatment of NPC in a subject, the subject having an ER-type missense mutation in the NPC gene.

[0057] In some embodiments, the method further comprises administering an additional active pharmaceutical ingredient selected from N-alkyl derivatives of 1,5-dideoxy-1,5-imino-D-glucitol, wherein the alkyl contains from 2 to 8 carbon atoms, stereoisomers thereof, and acid addition salts thereof.

[0058] Accordingly, also one aspect of 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, in combination with a further active pharmaceutical ingredient selected from N-alkyl derivatives of 1,5-dideoxy-1,5-imino-D-glucitol, wherein the alkyl contains 2 to 8 carbon atoms, its stereoisomers and acid addition salts thereof, for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an ER-type missense mutation in the NPC gene.

[0059] In some embodiments, the method further comprises administering an additional active pharmaceutical ingredient that is N-butyl-deoxynojirimycin (miglustat).

[0060] Thus, in some aspects of the disclosure, there is provided an active pharmaceutical ingredient that is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride and acid addition salts thereof, in combination with a further active pharmaceutical ingredient that is N-butyl-deoxynojirimycin (miglustat), for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an ER-type missense mutation in the NPC gene.

[0061] Thus, in some aspects of the disclosure, there is provided an active pharmaceutical ingredient that is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol), in combination with a further active pharmaceutical ingredient that is N-butyl-deoxynojirimycin (miglustat), for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an ER-type missense mutation in the NPC gene.

[0062] One aspect of the disclosure provides (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol), in combination with N-butyl-deoxynojirimycin (miglustat), for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an ER-type missense mutation in the NPC gene.

[0063] In some embodiments, the treatment is prophylactic. In some embodiments, the treatment is curative. In some embodiments, the treatment is ameliorative.

[0064] The progression of NPC in a subject can be tracked by clinicians using the NPC Composite Clinical Severity Scale (hereinafter "NPCCSS"; see Yanjanin et al.). The maximum "17-domain NPCCSS score" incorporates clinical signs and symptoms from nine major domains (gait, cognition, eye movement, fine motor, hearing, memory, seizures, language, swallowing) and eight minor domains (auditory brainstem response, behavior, cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) to determine a score that represents the severity of the progression of the subject's NPC (the higher the score, the more advanced / severe the disease). The summarized "5-domain NPCCSS score" has been used successfully by clinicians and incorporates clinical signs and symptoms from the major domains of gait, cognition, fine motor, language, and swallowing (see Cortina-Borja).

[0065] Subgroups of subjects in the NPC patient population can also be analyzed using the Annualized Incremental Severity Score (hereinafter "ASIS"), calculated by dividing the sum of the NPCCSS score by the age of the subject, to provide a measure of the rate of disease progression in individual subjects. The value obtained can therefore be an indicator of the rate of annual disease progression (see Cortina-Borja et al.).

[0066] In one embodiment, a subject with NPC has an ASIS of between about 0.5 and about 2.

[0067] In some embodiments of the present disclosure, there is provided an active pharmaceutical ingredient that is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol) for use in a method for treating or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject has an endoplasmic reticulum (ER)-type missense mutation in the NPC gene, and the subject has an ASIS of between about 0.5 and about 2.

[0068] In some embodiments of the disclosure, there is provided an active pharmaceutical ingredient that is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol), in combination with a further active pharmaceutical ingredient that is N-butyl-deoxynojirimycin (miglustat), for use in a method for treating or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject has an endoplasmic reticulum (ER)-type missense mutation in the NPC gene, and the subject has an ASIS of between about 0.5 and about 2.

[0069] In some embodiments, the disclosure provides a method for treating or preventing NPC in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an active pharmaceutical ingredient disclosed herein, wherein the subject has an ASIS of between about 0.5 and about 2.

[0070] In some embodiments, the disclosure provides a method for treating or preventing NPC in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an active pharmaceutical ingredient disclosed herein and a therapeutically effective amount of an additional active pharmaceutical ingredient disclosed herein, wherein the subject has an ASIS of between about 0.5 and about 2.

[0071] Active pharmaceutical ingredients (e.g., 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 its acid addition salts.

[0072] In some embodiments, the active pharmaceutical ingredient is a racemate of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0073] 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.

[0074] In some embodiments, the active pharmaceutical ingredient is an enantiomer of N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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 salts, (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.

[0081] In some embodiments, the active pharmaceutical ingredient is arimoclomol, also known as "BRX-345" or (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate. 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 free base citrate formulation, i.e., (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, which has the structure as shown in formula I: [ka]

[0082] Further active pharmaceutical ingredients (e.g. miglustat) The disclosure further provides for this purpose a combination comprising a further active pharmaceutical ingredient selected from N-alkyl derivatives of 1,5-dideoxy-1,5-imino-D-glucitol, wherein the alkyl contains from 2 to 8 carbon atoms, its stereoisomers and acid addition salts thereof.

[0083] In some embodiments, the alkyl group of the additional active pharmaceutical ingredient contains 4 to 6 carbon atoms.

[0084] In some embodiments, the alkyl group of the further active pharmaceutical ingredient is butyl. In some embodiments, the alkyl group of the further active pharmaceutical ingredient is hexyl.

[0085] In some embodiments, the further active pharmaceutical ingredient is N-butyl-deoxynojirimycin. N-butyl-deoxynojirimycin is also known as "OGT918", N-butylmoranoline, 1,5-(butylimino)-1,5-dideoxy-D-glucitol, (2R,3R,4R,5S)-1-butyl-2-(hydroxymethyl)piperidine-3,4,5-triol or miglustat. Thus, in some embodiments, the further active pharmaceutical ingredient has the chemical structure of formula II: [ka]

[0086] In some embodiments, the additional active pharmaceutical ingredient is an acid addition salt of N-butyl-deoxynojirimycin (miglustat).

[0087] In some embodiments, the additional active pharmaceutical ingredient is Zavesca® or Brazaves®.

[0088] In some embodiments, the additional active pharmaceutical ingredient is miglustat.

[0089] NPC Patient Subgroups The inventors have surprisingly found that a specific subgroup of NPC patients, specifically subjects carrying at least one ER-type missense mutation in at least one of the two alleles of the NPC gene, respond strongly to treatment with arimoclomol.

[0090] In some embodiments, ER-type missense mutations cause the NPC protein to be produced and misfolded, retained in the endoplasmic reticulum (ER), and subsequently targeted for degradation.

[0091] In some embodiments, the ER-type missense mutation results in the production of an NPC protein that is misfolded. In some embodiments, the ER-type missense mutation results in the production of an NPC protein that is retained in the endoplasmic reticulum (ER). In some embodiments, the ER-type missense mutation results in the production of an NPC protein that is targeted for degradation. In some embodiments, the ER-type missense mutation results in the production of an NPC protein that is misfolded, retained in the endoplasmic reticulum (ER), and / or subsequently targeted for degradation.

[0092] In some embodiments, the NPC protein is selected from the group consisting of NPC1 and NPC2. In some embodiments, the NPC protein is NPC1. In some embodiments, the NPC protein is NPC2.

[0093] In a specific embodiment, the NPC protein is NPC1 (SEQ ID NO:2).

[0094] In one embodiment 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 or preventing Niemann-Pick disease type C (NPC) in a subject having an NPC protein that is misfolded, retained in the endoplasmic reticulum (ER) and subsequently targeted for degradation. In one embodiment, the NPC protein is NPC1.

[0095] In one embodiment, there is provided an active pharmaceutical ingredient which is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol) for use in a method for treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an NPC protein that is misfolded, retained in the endoplasmic reticulum (ER) and subsequently targeted for degradation. In one embodiment, the NPC protein is NPC1.

[0096] In one embodiment, there is provided an active pharmaceutical ingredient which is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol), in combination with a further active pharmaceutical ingredient which is N-butyl-deoxynojirimycin (miglustat), for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject having NPC protein that is misfolded, retained in the endoplasmic reticulum (ER) and subsequently targeted for degradation. In one embodiment, the NPC protein is NPC1.

[0097] In some embodiments, the NPC gene is selected from the group consisting of NPC1 and NPC2. In some embodiments, the NPC gene is NPC1. In some embodiments, the NPC gene is NPC2.

[0098] In a specific embodiment, the NPC gene is NPC1 (SEQ ID NO:1).

[0099] In one embodiment, 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 or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an endoplasmic reticulum (ER)-type missense mutation in the NPC1 gene.

[0100] In one embodiment, there is provided an active pharmaceutical ingredient which is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol) for use in a method for treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject having an endoplasmic reticulum (ER)-type missense mutation in the NPC1 gene.

[0101] In one embodiment there is provided an active pharmaceutical ingredient which is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol), in combination with a further active pharmaceutical ingredient which is N-butyl-deoxynojirimycin (miglustat), for use in a method for the treatment or prevention of Niemann-Pick disease type C (NPC) in a subject, wherein the subject has an ER-type missense mutation in the NPC1 gene.

[0102] In some embodiments, the ER-type missense mutation results in a single amino acid change.

[0103] In some embodiments, the subject is homozygous for ER missense mutation. In some embodiments, the subject is heterozygous for ER missense mutation. In some embodiments, the subject has at least one ER missense mutation in each of two alleles of the NPC gene. In some embodiments, the subject has at least one ER missense mutation in one of two alleles of the NPC gene. In some embodiments, the subject has at least one ER missense mutation in one of two alleles of the NPC gene and a functional null mutation in the other allele of the NPC gene. In some embodiments, the subject is a compound heterozygote for the NPC gene.

[0104] The I1061T mutation is the most commonly reported mutation causing NPC, and in the homozygous state or in combination with a functional null allele, results in a clinical phenotype with late childhood or early juvenile onset and a “classic” increase in filipin staining in cultured fibroblasts (Imrie et al. 2007). This mutation causes the NPC1 protein to be misfolded and retained in the endoplasmic reticulum (ER), where it is subsequently targeted for degradation (Gelsthorpe et al. 2008; Schultz et al. 2018). Given that I1061T NPC1 function is preserved when properly trafficked to lysosomes (Gelsthorpe et al. 2008), such ER mutations may act in a positive dominant manner if treatment promotes their refolding, maturation, and localization to lysosomes.

[0105] In one embodiment, the ER-type missense mutation is selected from the group consisting of C113R, R389L, G535V, L724P, Q921P, W942C, G1034C, V378A, R404Q, H510P, Q775P, M1142T, N1156S, G1162V, R1186H, L1244P and I1061T.

[0106] In one embodiment, the ER-type missense mutation is selected from the group consisting of I1061T, M1142T, N1156S, and R1186H.

[0107] In some embodiments, the ER missense mutation is I1061T. In some embodiments, the ER missense mutation is M1142T. In some embodiments, the ER missense mutation is N1156S. In some embodiments, the ER missense mutation is R1186H.

[0108] In some embodiments, the subject is I1061T / E1188 * , I1061T / A1151T, I1061T / Q119fs, I1061T / I962fs, T1036M / I1061T, I1061T / V1141G, N968S / R1186H, N1156S / F1199sp2, Q991fs / I1061T, H1016L / I1061T, I1061T / A1192fs, I1061T / N1156S, R1186H / R1186H, P1007A / R1186H, and I1061T / D508fs.

[0109] In one embodiment 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 of treating or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject is selected from the group consisting of C113R, R389L, G535V, L724P, Q921P, W942C, G1034C, V378A, R404Q, H510P, Q775P, M1142T, N1156S, G1162V, R1186H, L1244P and I1061T. For example, a sequence selected from the group consisting of I1061T, M1142T, N1156S, and R1186H. For example, I1061T, For example, M1142T, For example, N1156S, For example, R1186H, The patient has an endoplasmic reticulum (ER)-type missense mutation in the NPC1 gene.

[0110] In one embodiment there is provided an active pharmaceutical ingredient which is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol) for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject is a patient selected from the group consisting of C113R, R389L, G535V, L724P, Q921P, W942C, G1034C, V378A, R404Q, H510P, Q775P, M1142T, N1156S, G1162V, R1186H, L1244P and I1061T. For example, a sequence selected from the group consisting of I1061T, M1142T, N1156S, and R1186H. For example, I1061T, For example, M1142T, For example, N1156S, For example, R1186H, The patient has an endoplasmic reticulum (ER)-type missense mutation in the NPC1 gene.

[0111] In one embodiment there is provided an active pharmaceutical ingredient which is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol), in combination with a further active pharmaceutical ingredient which is N-butyl-deoxynojirimycin (miglustat), for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject is For example, a sequence selected from the group consisting of I1061T, M1142T, N1156S, and R1186H. For example, I1061T, For example, M1142T, For example, N1156S, For example, R1186H, This patient has an ER-type missense mutation in the NPC1 gene.

[0112] In one embodiment, 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 or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject is * , I1061T / A1151T, I1061T / Q119fs, I1061T / I962fs, T1036M / I1061T, I1061T / V1141G, N968S / R1186H, N1156S / F1199sp2, Q991fs / I1061T, H1016L / I1061T, I1061T / A1192fs, I1061T / N1156S, R1186H / R1186H, P1007A / R1186H, and I1061T / D508fs.

[0113] In one embodiment, there is provided an active pharmaceutical ingredient which is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol) for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, the subject being administered I1061T / E1188 * , I1061T / A1151T, I1061T / Q119fs, I1061T / I962fs, T1036M / I1061T, I1061T / V1141G, N968S / R1186H, N1156S / F1199sp2, Q991fs / I1061T, H1016L / I1061T, I1061T / A1192fs, I1061T / N1156S, R1186H / R1186H, P1007A / R1186H, and I1061T / D508fs.

[0114] In one embodiment, there is provided an active pharmaceutical ingredient that is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol), in combination with a further active pharmaceutical ingredient that is N-butyl-deoxynojirimycin (miglustat), for use in a method of treating or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject is * , I1061T / A1151T, I1061T / Q119fs, I1061T / I962fs, T1036M / I1061T, I1061T / V1141G, N968S / R1186H, N1156S / F1199sp2, Q991fs / I1061T, H1016L / I1061T, I1061T / A1192fs, I1061T / N1156S, R1186H / R1186H, P1007A / R1186H, and I1061T / D508fs.

[0115] In some embodiments, determining the NPC genotype (e.g., NPC1 genotype and / or NPC2 genotype) comprises sequencing nucleic acid isolated from a biological sample from the subject. As will be appreciated by one of skill in the art, the NPC genotype (e.g., NPC1 genotype and / or NPC2 genotype) can be determined using any genotyping method known in the art.

[0116] In some embodiments, the subject or patient is a mammal, hi some embodiments, the subject or patient is a human.

[0117] In some embodiments, the subject or patient is about 1 year old or older, such as about 2 years old or older, such as about 3 years old or older, such as about 4 years old or older, such as about 5 years old or older, such as about 6 years old or older, such as about 7 years old or older, such as about 8 years old or older, such as about 9 years old or older, such as about 10 years old or older. In certain embodiments, the subject or patient is about 4 years old or older.

[0118] In some embodiments, the subject is about 1 year old. In some embodiments, the subject is about 2 years old. In some embodiments, the subject is about 3 years old. In some embodiments, the subject is about 4 years old. In some embodiments, the subject is about 5 years old. In some embodiments, the subject is about 6 years old. In some embodiments, the subject is about 7 years old. In some embodiments, the subject is about 8 years old. In some embodiments, the subject is about 9 years old. In some embodiments, the subject is about 10 years old. In some embodiments, the subject is about 11 years old. In some embodiments, the subject is about 12 years old. In some embodiments, the subject is about 13 years old. In some embodiments, the subject is about 14 years old. In some embodiments, the subject is about 15 years old. In some embodiments, the subject is about 16 years old. In some embodiments, the subject is about 17 years old. In some embodiments, the subject is about 18 years old. In some embodiments, the subject is about 19 years old. In some embodiments, the subject is about 20 years old. In some embodiments, the subject is about 21 years old. In some embodiments, the subject is about 22 years old. In some embodiments, the subject is about 23 years old. In some embodiments, the subject is about 24 years old. In some embodiments, the subject is about 25 years old. In some embodiments, the subject is about 26 years old. In some embodiments, the subject is about 27 years old. In some embodiments, the subject is about 28 years old. In some embodiments, the subject is about 29 years old. In some embodiments, the subject is about 30 years old.

[0119] In some embodiments, the subject is between about 0 and about 5 years of age. In some embodiments, the subject is between about 5 and about 10 years of age. In some embodiments, the subject is between about 10 and about 15 years of age. In some embodiments, the subject is between about 15 and about 20 years of age. In some embodiments, the subject is between about 20 and about 30 years of age. In some embodiments, the subject is between about 30 and about 40 years of age. In some embodiments, the subject is between about 40 and about 50 years of age. In some embodiments, the subject is between about 50 and about 60 years of age. In some embodiments, the subject is between about 60 and about 70 years of age. In some embodiments, the subject is between about 70 and about 80 years of age. In some embodiments, the subject is between about 80 and about 90 years of age. In some embodiments, the subject is between about 90 and about 100 years of age. In some embodiments, the subject is between about 100 and about 110 years of age.

[0120] formulation While it is possible for active pharmaceutical ingredients to be administered as raw chemicals, in some embodiments it is preferable to present them in the form of a pharmaceutical formulation.

[0121] Accordingly, compositions such as pharmaceutical compositions, i.e. pharma- ceutical safe compositions, comprising an active pharmaceutical ingredient as defined herein for use in a method for treating or preventing NPC in a subject, the subject having an ER-type missense mutation in the NPC gene.

[0122] Also provided herein are compositions, such as pharmaceutical compositions, i.e. pharma- ceutical safe compositions, comprising an active pharmaceutical ingredient as defined herein and a further active pharmaceutical ingredient as defined herein, separately or together.

[0123] In some embodiments, the composition further comprises a pharma- ceutically and / or physiologically acceptable diluent, carrier and / or excipient.

[0124] In some embodiments, the compositions are formulated for oral administration, such as in the form of a tablet or capsule, or a powder, e.g., a powder suitable for suspension in a liquid, or for oral administration.

[0125] In some embodiments, the composition is formulated as a liquid for injection.

[0126] Pharmaceutical compositions containing the active pharmaceutical ingredient of the present invention and, optionally, further active pharmaceutical ingredients, may be prepared by conventional techniques.

[0127] Administration and Dosage The active pharmaceutical ingredients disclosed herein, or compositions comprising the same as defined herein, are, in some embodiments, administered to a subject in need thereof in a pharma- ceutical or therapeutically effective amount.

[0128] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered for more than 1 week, such as more than 2 weeks, such as more than 3 weeks, such as more than 4 weeks.

[0129] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered for more than 1 month, such as more than 2 months, for example more than 3 months, such as more than 4 months, for example more than 5 months, for example more than 6 months.

[0130] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered for more than 1 year, such as more than 2 years, such as more than 3 years, such as more than 4 years, such as 5 years or more.

[0131] In some embodiments, treatment comprises initiating early treatment with an active pharmaceutical ingredient disclosed herein, in other words, in some embodiments, treatment with an active pharmaceutical ingredient disclosed herein is initiated shortly after presentation of symptoms and / or a diagnosis of NPC.

[0132] In one embodiment, the dose is calculated based on arimoclomol citrate ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate).

[0133] In one embodiment, the dose is calculated based on arimoclomol free base ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride).

[0134] In some embodiments, the active pharmaceutical ingredient is administered as described in Table A.

[0135] In some embodiments, the active pharmaceutical ingredient is administered as described in Table B.

[0136] [Table 1] [Table 2]

[0137] Dose, Arimoclomol (Citrate) In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 25 mg / day to about 1000 mg / day. In a preferred embodiment, the active pharmaceutical ingredient is arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate).

[0138] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 150 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 200 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 250 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 350 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 400 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 450 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 500 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 550 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 600 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 650 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 700 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 750 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 800 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 850 mg / day to about 1000 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 900 mg / day to about 1000 mg / day.In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 950 mg / day to about 1000 mg / day. In a preferred embodiment, the active pharmaceutical ingredient is arimoclomol.

[0139] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 950 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 900 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 850 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 800 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 750 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 700 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 650 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 600 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 550 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 500 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 450 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 400 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 350 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 300 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 250 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 200 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day to about 150 mg / day.In a preferred embodiment, the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol).

[0140] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 100 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 125 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 150 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 175 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 200 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 225 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 250 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 275 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 325 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 350 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 375 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 400 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 425 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 450 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 475 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 500 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 525 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 550 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 575 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 600 mg / day.In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 625 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 650 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 675 mg / day. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at about 700 mg / day. In a preferred embodiment, the active pharmaceutical ingredient is arimoclomol.

[0141] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 50 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 75 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 125 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 150 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 175 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 200 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered in a dose of about 225 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered in a dose of about 250 mg to about 300 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered in a dose of about 275 mg to about 300 mg. In a preferred embodiment, the active pharmaceutical ingredient is arimoclomol.

[0142] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 275 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 250 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 225 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 200 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 175 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 150 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 125 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg to about 100 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered in a dose of about 25 mg to about 75 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered in a dose of about 25 mg to about 50 mg. In a preferred embodiment, the active pharmaceutical ingredient is arimoclomol.

[0143] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 25 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 50 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 75 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 125 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 150 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 175 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 200 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 225 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered within a dose of about 250 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered in a dose of about 275 mg. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered in a dose of about 300 mg. In a preferred embodiment, the active pharmaceutical ingredient is arimoclomol.

[0144] In some embodiments, the subject weighs about 8 kg to about 15 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0145] In some embodiments, the subject has a body weight of about 8 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the subject has a body weight of about 9 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the subject has a body weight of about 10 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the subject has a body weight of about 11 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the subject has a body weight of about 12 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the subject has a body weight of about 13 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the subject has a body weight of about 14 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the subject has a body weight of about 15 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 50 mg tid (i.e., about 150 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0146] In some embodiments, the subject weighs about 15 kg to about 22 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0147] In some embodiments, the subject has a body weight of about 15 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the subject has a body weight of about 16 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the subject has a body weight of about 17 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the subject has a body weight of about 18 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the subject has a body weight of about 19 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the subject has a body weight of about 20 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the subject has a body weight of about 21 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the subject has a body weight of about 22 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0148] In some embodiments, the subject weighs about 22 kg to about 38 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate salt).

[0149] In some embodiments, the subject has a body weight of about 22 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 23 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 24 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 25 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 26 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 27 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 28 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 29 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 30 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 31 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 32 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (ie, about 300 mg / day).In some embodiments, the subject has a body weight of about 33 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 34 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 35 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 36 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 37 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the subject has a body weight of about 38 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0150] In some embodiments, the subject weighs about 38 kg to about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0151] In some embodiments, the subject has a body weight of about 38 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 39 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 40 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 41 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 42 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 43 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 44 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 45 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 46 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 47 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 48 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (ie, about 450 mg / day).In some embodiments, the subject has a body weight of about 49 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 50 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 51 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 52 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 53 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 54 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the subject has a body weight of about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0152] In some embodiments, the subject weighs more than about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 200 mg tid (i.e., about 600 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0153] In some embodiments, the subject weighs about 8 kg to about 15 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 75 mg tid (i.e., about 225 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate salt).

[0154] In some embodiments, the subject weighs about 15 kg to about 30 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 100 mg tid (i.e., about 300 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate salt).

[0155] In some embodiments, the subject weighs about 30 kg to about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 150 mg tid (i.e., about 450 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0156] In some embodiments, the subject weighs more than about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 200 mg tid (i.e., about 600 mg / day). In some embodiments, the active pharmaceutical ingredient is arimoclomol (citrate).

[0157] Dose, Arimoclomol (free base) In some embodiments, the active ingredient is arimoclomol free base form (not a specific salt form), i.e., (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, and the dose is calculated based on the free base form.

[0158] A reference to arimoclomol free base form, i.e., (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, includes all acid addition salts thereof.

[0159] In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 63 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 73 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 83 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 93 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 103 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 113 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 123 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 133 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 143 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 153 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 163 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 173 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 183 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 193 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 203 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 213 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 223 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 243 mg / day to about 423 mg / day.In some embodiments, the arimoclomol free base form is administered at about 253 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 263 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 273 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 283 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 293 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 303 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 313 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 323 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 333 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 343 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 353 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 363 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 373 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 383 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 393 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 403 mg / day to about 423 mg / day. In some embodiments, the arimoclomol free base form is administered at about 413 mg / day to about 423 mg / day.

[0160] In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 413 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 403 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 393 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 383 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 373 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 363 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 353 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 343 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 333 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 323 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 313 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 303 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 293 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 283 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 273 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 263 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 253 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 243 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 233 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 223 mg / day.In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 213 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 203 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 193 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 183 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 173 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 163 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 153 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 143 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 133 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 123 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 113 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 103 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 93 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 83 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 73 mg / day. In some embodiments, the arimoclomol free base form is administered at about 53 mg / day to about 63 mg / day.

[0161] In some embodiments, the arimoclomol free base form is about 53 mg / day, about 63 mg / day, about 73 mg / day, about 83 mg / day, about 93 mg / day, about 103 mg / day, about 113 mg / day, about 123 mg / day, about 133 mg / day, about 134 mg / day, about 143 mg / day, about 153 mg / day, about 163 mg / day, about 173 mg / day, about 183 mg / day, about 193 mg / day, about 203 mg / day, about 213 mg / day, about 223 mg / day, about 230 mg / day, about 240 mg / day, about 250 mg / day, about 260 mg / day, about 270 mg / day, about 280 mg / day, about 290 mg / day, about 300 mg / day, about 310 mg / day, about 320 mg / day, about 330 mg / day, about 340 mg / day, about 350 mg / day, about 360 mg / day, about 370 mg / day, about 380 mg / day, about 390 mg / day, about 400 mg / day, about 410 mg / day, about 420 mg / day, about 430 mg / day, about 440 mg / day, about 450 mg / day, about 460 mg / day, about 470 mg / day, about 480 mg / day, about 490 mg / day, about 500 mg / day, about 510 mg / day, about 520 mg / day, about 530 mg / day, about 540 mg / day, about 550 mg / day, about 560 mg / day, about 570 mg / day, about 580 mg / day, about 590 mg / daily, about 233 mg / day, about 243 mg / day, about 253 mg / day, about 263 mg / day, about 273 mg / day, about 283 mg / day, about 293 mg / day, about 303 mg / day, about 313 mg / day, about 323 mg / day, about 333 mg / day, about 343 mg / day, about 353 mg / day, about 363 mg / day, about 373 mg / day, about 383 mg / day, about 393 mg / day, about 403 mg / day, about 413 mg / day, or about 423 mg / day.

[0162] In some embodiments, the arimoclomol free base form is administered at about 53 mg / day. In some embodiments, the arimoclomol free base form is administered at about 63 mg / day. In some embodiments, the arimoclomol free base form is administered at about 73 mg / day. In some embodiments, the arimoclomol free base form is administered at about 83 mg / day. In some embodiments, the arimoclomol free base form is administered at about 93 mg / day. In some embodiments, the arimoclomol free base form is administered at about 103 mg / day. In some embodiments, the arimoclomol free base form is administered at about 113 mg / day. In some embodiments, the arimoclomol free base form is administered at about 123 mg / day. In some embodiments, the arimoclomol free base form is administered at about 133 mg / day. In some embodiments, the arimoclomol free base form is administered at about 134 mg / day. In some embodiments, the arimoclomol free base form is administered at about 143 mg / day. In some embodiments, the arimoclomol free base form is administered at about 153 mg / day. In some embodiments, the arimoclomol free base form is administered at about 163 mg / day. In some embodiments, the arimoclomol free base form is administered at about 173 mg / day. In some embodiments, the arimoclomol free base form is administered at about 183 mg / day. In some embodiments, the arimoclomol free base form is administered at about 193 mg / day. In some embodiments, the arimoclomol free base form is administered at about 203 mg / day. In some embodiments, the arimoclomol free base form is administered at about 213 mg / day. In some embodiments, the arimoclomol free base form is administered at about 223 mg / day. In some embodiments, the arimoclomol free base form is administered at about 233 mg / day. In some embodiments, the arimoclomol free base form is administered at about 243 mg / day. In some embodiments, the arimoclomol free base form is administered at about 253 mg / day. In some embodiments, the arimoclomol free base form is administered at about 263 mg / day.In some embodiments, the arimoclomol free base form is administered at about 273 mg / day. In some embodiments, the arimoclomol free base form is administered at about 283 mg / day. In some embodiments, the arimoclomol free base form is administered at about 293 mg / day. In some embodiments, the arimoclomol free base form is administered at about 303 mg / day. In some embodiments, the arimoclomol free base form is administered at about 313 mg / day. In some embodiments, the arimoclomol free base form is administered at about 323 mg / day. In some embodiments, the arimoclomol free base form is administered at about 333 mg / day. In some embodiments, the arimoclomol free base form is administered at about 343 mg / day. In some embodiments, the arimoclomol free base form is administered at about 353 mg / day. In some embodiments, the arimoclomol free base form is administered at about 363 mg / day. In some embodiments, the arimoclomol free base form is administered at about 373 mg / day. In some embodiments, the arimoclomol free base form is administered at about 383 mg / day. In some embodiments, the arimoclomol free base form is administered at about 393 mg / day. In some embodiments, the arimoclomol free base form is administered at about 403 mg / day. In some embodiments, the arimoclomol free base form is administered at about 413 mg / day. In some embodiments, the arimoclomol free base form is administered at about 423 mg / day.

[0163] In some embodiments, the arimoclomol free base form is administered at about 372 mg / day.

[0164] In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 23 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 33 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 43 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 53 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 63 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 73 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 83 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 93 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 103 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 113 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 123 mg to about 143 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 133 mg to about 143 mg.

[0165] In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 133 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 123 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 113 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 103 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 93 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 83 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 73 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg to about 63 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 13 mg to about 53 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 13 mg to about 43 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 13 mg to about 33 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 13 mg to about 23 mg.

[0166] In some embodiments, the arimoclomol free base form is administered within a dose of about 13 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 23 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 33 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 43 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 53 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 63 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 73 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 83 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 93 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 103 mg. In some embodiments, the arimoclomol free base form is administered within a dose of about 113 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 123 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 133 mg. In some embodiments, the arimoclomol free base form is administered in a dose of about 143 mg.

[0167] In some embodiments, the arimoclomol free base form is administered in a dose of about 124 mg.

[0168] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least one day per week. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least two days per week. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least three days per week. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least four days per week. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least five days per week. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least six days per week. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least seven days per week.

[0169] In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least once daily. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least twice daily. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least three times daily. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least four times daily. In some embodiments, the active pharmaceutical ingredient disclosed herein is administered at least five times daily.

[0170] In some embodiments, the active pharmaceutical ingredients disclosed herein are administered three times daily (tid).

[0171] In some embodiments, arimoclomol is administered at least once daily. In some embodiments, arimoclomol is administered at least twice daily. In some embodiments, arimoclomol is administered at least three times daily. In some embodiments, arimoclomol is administered at least four times daily. In some embodiments, arimoclomol is administered at least five times daily.

[0172] In some embodiments, the arimoclomol free base form is administered at least once daily. In some embodiments, the arimoclomol free base form is administered at least twice daily. In some embodiments, the arimoclomol free base form is administered at least three times daily. In some embodiments, the arimoclomol free base form is administered at least four times daily. In some embodiments, the arimoclomol free base form is administered at least five times daily.

[0173] In some embodiments, the arimoclomol free base form is administered from about 93 mg / day to about 372 mg / day three times daily.

[0174] In some embodiments, arimoclomol is administered at least one day per week. In some embodiments, arimoclomol is administered at least two days per week. In some embodiments, arimoclomol is administered at least three days per week. In some embodiments, arimoclomol is administered at least four days per week. In some embodiments, arimoclomol is administered at least five days per week. In some embodiments, arimoclomol is administered at least six days per week. In some embodiments, arimoclomol is administered at least seven days per week.

[0175] In some embodiments, the arimoclomol free base form is administered at least one day per week. In some embodiments, the arimoclomol free base form is administered at least two days per week. In some embodiments, the arimoclomol free base form is administered at least three days per week. In some embodiments, the arimoclomol free base form is administered at least four days per week. In some embodiments, the arimoclomol free base form is administered at least five days per week. In some embodiments, the arimoclomol free base form is administered at least six days per week. In some embodiments, the arimoclomol free base form is administered at least seven days per week.

[0176] In some embodiments, the active pharmaceutical ingredients disclosed herein are administered in a dose adjusted by the patient's weight. Thus, in some embodiments, arimoclomol is administered in a dose adjusted by the patient's weight. Similarly, in some embodiments, arimoclomol free base form is administered in a dose adjusted by the patient's weight.

[0177] In some embodiments, the subject has a body weight of about 8 kg to about 15 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 31 mg tid (i.e., about 93 mg / day), calculated as arimoclomol free base.

[0178] In some embodiments, the subject has a body weight of about 15 kg to about 22 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 47 mg tid (i.e., about 141 mg / day), calculated as arimoclomol free base.

[0179] In some embodiments, the subject has a body weight of about 22 kg to about 38 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 62 mg tid (i.e., about 186 mg / day), calculated as arimoclomol free base.

[0180] In some embodiments, the subject has a body weight of about 38 kg to about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 93 mg tid (i.e., about 279 mg / day), calculated as arimoclomol free base.

[0181] In some embodiments, the subject has a body weight greater than about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 124 mg tid (i.e., about 372 mg / day), calculated as arimoclomol free base.

[0182] In some embodiments, the subject has a body weight of about 8 kg to about 15 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 47 mg tid (i.e., about 141 mg / day), calculated as arimoclomol free base.

[0183] In some embodiments, the subject has a body weight of about 15 kg to about 30 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 62 mg tid (i.e., about 186 mg / day), calculated as arimoclomol free base.

[0184] In some embodiments, the subject has a body weight of about 30 kg to about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 93 mg tid (i.e., about 279 mg / day), calculated as arimoclomol free base.

[0185] In some embodiments, the subject has a body weight greater than about 55 kg and the active pharmaceutical ingredient disclosed herein is administered at a dose of about 124 mg tid (i.e., about 372 mg / day), calculated as arimoclomol free base.

[0186] Dosage, further active pharmaceutical ingredients In some embodiments, an additional active pharmaceutical ingredient is administered to the subject. In a preferred embodiment, the additional active pharmaceutical ingredient is miglustat.

[0187] In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 350 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 400 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 450 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 500 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 550 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 600 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 650 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 700 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 750 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 800 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 850 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 900 mg / day to about 1000 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 950 mg / day to about 1000 mg / day. In a preferred embodiment, the additional active pharmaceutical ingredient disclosed herein is miglustat.

[0188] In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 950 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 900 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 850 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 800 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 750 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 700 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 650 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 600 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 550 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 500 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 450 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 400 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day to about 350 mg / day. In a preferred embodiment, the additional active pharmaceutical ingredient disclosed herein is miglustat.

[0189] In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 300 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 325 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 350 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 375 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 400 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 425 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 450 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 475 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 500 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 525 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 550 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 575 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 600 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 625 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 650 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 675 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 700 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 725 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 750 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 775 mg / day.In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 800 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 825 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 850 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 875 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 900 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 925 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 950 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 975 mg / day. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered at about 1000 mg / day. In a preferred embodiment, the additional active pharmaceutical ingredient disclosed herein is miglustat.

[0190] In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 300 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 125 mg to about 300 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 150 mg to about 300 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 175 mg to about 300 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 200 mg to about 300 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 225 mg to about 300 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 250 mg to about 300 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 275 mg to about 300 mg. In a preferred embodiment, the additional active pharmaceutical ingredient disclosed herein is miglustat.

[0191] In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 275 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 250 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 225 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 200 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 175 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 150 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg to about 125 mg. In a preferred embodiment, the additional active pharmaceutical ingredient disclosed herein is miglustat.

[0192] In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 100 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 125 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 150 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 175 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 200 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 225 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 250 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 275 mg. In some embodiments, the additional active pharmaceutical ingredient disclosed herein is administered within a dose of about 300 mg. In a preferred embodiment, the additional active pharmaceutical ingredient disclosed herein is miglustat.

[0193] In some embodiments, the dose of the additional active pharmaceutical ingredient, such as miglustat, is adjusted for subjects under 12 years of age based on body surface area.

[0194] Simultaneous administration In some embodiments, the active pharmaceutical ingredient and the further active pharmaceutical ingredient are administered simultaneously. In some embodiments, the active pharmaceutical ingredient and the further active pharmaceutical ingredient are administered close in time. In some embodiments, the further active pharmaceutical ingredient is administered before the active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient is administered before the further active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient and the further active pharmaceutical ingredient are administered simultaneously or sequentially. In some embodiments, the active pharmaceutical ingredient is arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate) and the further active pharmaceutical ingredient is miglustat. In some embodiments, the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride and the further active pharmaceutical ingredient is miglustat.

[0195] In some embodiments, the additional active pharmaceutical ingredient is administered at least 6 months prior to the first administration of the active pharmaceutical ingredient. In some embodiments, the additional active pharmaceutical ingredient is administered at least 1 year prior to the first administration of the active pharmaceutical ingredient. In some embodiments, the additional active pharmaceutical ingredient is administered at least 2 years prior to the first administration of the active pharmaceutical ingredient. In some embodiments, the active pharmaceutical ingredient is arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate) and the additional active pharmaceutical ingredient is miglustat. In some embodiments, the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride and the additional active pharmaceutical ingredient is miglustat.

[0196] In some embodiments, the active pharmaceutical ingredients disclosed herein are administered orally. In some embodiments, the active pharmaceutical ingredients disclosed herein are administered via a feeding tube.

[0197] Efficacy of treatment In some embodiments, administration of an active pharmaceutical ingredient disclosed herein provides sustained benefits over a period of time. In some embodiments, the period is six months. In some embodiments, the period is one year. In some embodiments, the period is one year and six months. In some embodiments, the period is two years. In some embodiments, the period is two years and six months. In some embodiments, the period is three years. In some embodiments, the active pharmaceutical ingredient is arimoclomol.

[0198] In some embodiments, the course of the disease is ameliorated by the treatments disclosed herein.

[0199] In some embodiments, administration of the active pharmaceutical ingredient reduces the accumulation of non-esterified cholesterol. In some embodiments, the reduction of non-esterified cholesterol occurs in peripheral blood mononuclear cells (PBMCs). In some aspects, administration of the active pharmaceutical ingredient reduces non-esterified cholesterol such that any increase in non-esterified cholesterol exhibited by the subject is about 10,000 ng / mg protein or less, or about 15,000 ng / mg protein or less, or about 20,000 ng / mg protein or less, or about 25,000 ng / mg protein or less, or about 30,000 ng / mg protein or less, or about 35,000 ng / mg protein or less, or about 40,000 ng / mg protein or less. In some embodiments, the active pharmaceutical ingredient is arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate). In some embodiments, the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0200] In some embodiments, administration of the active pharmaceutical ingredient reduces the serum cholestanetriol accumulation level. In some embodiments, administration of the active pharmaceutical ingredient reduces the serum cholestanetriol accumulation level such that there is a decrease of at least about 2.5ng / ml, or a decrease of at least about 3.0ng / ml, or a decrease of at least about 3.5ng / ml, or a decrease of at least about 4.0ng / ml, or a decrease of at least about 4.5ng / ml, or a decrease of at least about 5.0ng / ml, or a decrease of at least about 5.5ng / ml, or a decrease of at least about 6.0ng / ml, or a decrease of at least about 6.5ng / ml, or a decrease of at least about 7.0ng / ml, or a decrease of at least about 7.5ng / ml, or a decrease of at least about 7.5ng / ml, or a decrease of at least about 8.0ng / ml, or a decrease of at least about 8.5ng / ml, or a decrease of at least about 9.0ng / ml, or a decrease of at least about 9.5ng / ml, or a decrease of at least about 10.0ng / ml. In some embodiments, the active pharmaceutical ingredient is arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate). In some embodiments, the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0201] In some embodiments, administration of the active pharmaceutical ingredient ameliorates the course of NPC such that a subject receiving the active pharmaceutical ingredient shows an increase in NPCCSS score over the course of treatment of about 0.1, such as about 0.2, for example about 0.3, such as about 0.4, for example about 0.5, such as about 0.6, for example about 0.7, such as about 0.8, for example about 0.9, such as about 1.0, for example about 1.1, such as about 1.2, for example about 1.3, such as about 1.4, for example about 1.5, such as about 1.6, for example about 1.7, such as about 1.8, for example about 1.9, such as about 2.0 or less. In some embodiments, the course of treatment can be at least about 1 month, such as about 2 months, such as about 3 months, such as about 4 months, such as about 5 months, such as about 6 months, such as about 7 months, such as about 8 months, such as about 9 months, such as about 10 months, such as about 11 months, such as about 12 months, such as about 13 months, such as about 14 months, such as about 15 months, such as about 16 months, such as about 17 months, such as about 18 months, such as about 19 months, such as about 20 months, such as about 21 months, such as about 22 months, such as about 23 months, such as about 24 months. In some embodiments, the course of treatment can be more than 24 months. The NPCCSS score can be a 5-domain NPCCSS score or a 17-domain NPCCSS score, as described herein. In some embodiments, the active pharmaceutical ingredient is arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate). In some embodiments, the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0202] In some embodiments, administration of the active pharmaceutical ingredient results in a sustained benefit over a two-year period, characterized by the subject exhibiting an increase in the five-domain NPCCSS score of 1 or less over the two-year period. In some embodiments, the active pharmaceutical ingredient is arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate). In some embodiments, the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0203] In some embodiments, treatment with the active pharmaceutical ingredient increases properly matured NPC protein. In some embodiments, treatment with the active pharmaceutical ingredient increases properly matured NPC1 protein. In some embodiments, treatment with the active pharmaceutical ingredient increases properly matured NPC2 protein. In some embodiments, the active pharmaceutical ingredient is arimoclomol ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate). In some embodiments, the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.

[0204] Methods for predicting response to treatment or identifying subjects likely to respond to treatment

[0013] Also, one aspect of the present disclosure is to provide a method for predicting the responsiveness of a subject with Niemann-Pick disease type C (NPC) to treatment with arimoclomol, the method comprising: a) determining whether a subject has an ER-type missense mutation in the NPC gene; b) predicting that the subject will respond to treatment with arimoclomol if the subject is determined to have an ER missense mutation in the NPC gene; and Includes.

[0205] In some aspects, a method of predicting responsiveness to treatment with a combination of arimoclomol and miglustat in a subject with Niemann-Pick disease type C (NPC) is provided, the method comprising: a) determining whether a subject has an ER-type missense mutation in the NPC gene; b) predicting that a subject will respond to treatment with a combination of arimoclomol and miglustat if the subject is determined to have an ER-type missense mutation in the NPC gene; and Includes.

[0206] In some embodiments, a method is provided for identifying a subject with Niemann-Pick disease type C (NPC) that is likely to be responsive to treatment with arimoclomol, the method comprising: a) determining whether a subject has an ER-type missense mutation in the NPC gene; b) identifying the subject as likely to respond to treatment with arimoclomol if the subject is determined to have an ER missense mutation in the NPC gene; Includes.

[0207] In some aspects, a method is provided for identifying a subject with Niemann-Pick disease type C (NPC) likely to be responsive to treatment with a combination of arimoclomol and miglustat, the method comprising: a) determining whether a subject has an ER-type missense mutation in the NPC gene; b) if the subject is determined to have an ER-type missense mutation in the NPC gene, identifying the subject as likely to respond to treatment with a combination of arimoclomol and miglustat; Includes.

[0208] In some embodiments, the subject has an ER-type missense mutation in the NPC1 gene.In some embodiments, the subject has an ER-type missense mutation in the NPC2 gene.

[0209] In some embodiments, determining the NPC genotype (e.g., NPC1 genotype and / or NPC2 genotype) comprises sequencing nucleic acid isolated from a biological sample from the subject. As will be appreciated by one of skill in the art, the NPC genotype (e.g., NPC1 genotype and / or NPC2 genotype) can be determined using any genotyping method known in the art, such as DNA sequencing.

[0210] In some embodiments, the subject is identified as homozygous for an ER missense mutation. In some embodiments, the subject is identified as heterozygous for an ER missense mutation. In some embodiments, the subject is identified as having at least one ER missense mutation in each of the two alleles of the NPC gene. In some embodiments, the subject is identified as having at least one ER missense mutation in one of the two alleles of the NPC gene. In some embodiments, the subject is identified as compound heterozygous for an ER missense mutation in the NPC gene.

[0211] In one embodiment, the method further comprises one or more steps of administering arimoclomol. In another embodiment, the method further comprises one or more steps of administering arimoclomol and miglustat. EXAMPLES

[0212] Example 1 – Multinational clinical trial of Arimoclomol for the treatment of NPC The following example describes a 12-month, prospective, randomized, double-blind, placebo-controlled, Phase 2 / 3 multinational clinical trial conducted to test the use of arimoclomol for the treatment of Niemann-Pick disease type C (NPC).

[0213] method Study Participants: The NPC1 genotypes of subjects enrolled in the study are shown in Table 1. Patients enrolled in the trial were stratified by baseline use of miglustat. Patients in both strata were randomized 2:1 to receive arimoclomol or placebo. [Table 3] TIFF2024502304000006.tif214160TIFF2024502304000007.tif96160

[0214] Study Procedures: The screening visit (Visit 1) included baseline assessments, randomization, and pharmacokinetic (PK) assessments. The first dose of arimoclomol or placebo was administered within 1 week of randomization. Safety assessments were performed at Visit 2 (7-14 days after treatment initiation) and then every 3 months (Visits 3-6) during the blinded period. Telephone follow-up was conducted monthly to assess safety, verify patient weight, and evaluate treatment compliance.

[0215] Routine clinical care (including administration of miglustat) was maintained throughout the trial. Each participant was randomly assigned to receive arimoclomol or placebo three times daily. Arimoclomol (calculated as the free base) was administered orally or via feeding tube at doses ranging from 93 to 372 mg / day based on patient weight, up to an estimated adult equivalent of 372 mg / day or 124 mg three times daily.

[0216] During the 12-month treatment phase, efficacy assessments of the primary outcome, the 5-domain NPCCSS score, and the Non-Disease Specific Clinical Global Impression-Improvement Scale (CGI-I) score were performed at baseline and after 3, 6, 9, and 12 months of treatment. All other efficacy and biomarker assessments were performed at baseline and after 6 and 12 months of treatment.

[0217] Outcomes Primary Outcome: The primary outcome was the change from baseline in NPC severity at 12 months as assessed by the 5-domain NPCCSS score, a brief assessment tool derived from the 17-domain NPCCSS score developed by Yanjanin et al., as described herein. The fully validated 5-domain NPCCSS score includes the domains determined to be most clinically relevant to patients, caregivers, and clinicians: gait, cognition, fine motor skills, language, and swallowing. The sum of the 5-domain NPCCSS score ranges from 0 to 25, with higher scores indicating more severe clinical impairment.

[0218] Subgroup analysis of primary endpoint: NPC is a heterogeneous disease, with patients aged 2 to 18 years showing a wide spectrum of disease manifestations. The <4 years children group includes patients with mild symptoms and those with aggressive, early fatal disease. As this group is particularly heterogeneous, we predefined a subgroup of patients aged ≥4 years in the study participant population.

[0219] In the EU, miglustat is indicated for the treatment of progressive neurological symptoms in patients with NPC. However, as not all patients are candidates for miglustat treatment, it is recommended that the benefit of treatment be evaluated periodically (e.g., every 6 months). To elucidate the effect of arimoclomol in patients receiving miglustat treatment in the background, we prespecified an analysis of the subpopulation of patients receiving miglustat. Overall, the subgroup of patients aged ≥4 years and miglustat-treated patients was expected to be more homogenous with regard to baseline demographic and disease characteristics and therefore more suitable for comparison.

[0220] We also performed two post-hoc subgroup analyses.

[0221] In the first post hoc analysis, subjects with double null-of-function mutations in NPC1 (null-of-function / null-of-function NPC1 genotype) were excluded.

[0222] A second post-hoc analysis included only subjects with an Annualized Incremental Severity Score (ASIS) between 0.5 and 2.0. Cortina-Borja et al. suggest that stratifying the study cohort by applying a differential ASIS cut-off point of 0.5 to 2.0, which excludes very mild and very severe patients, could result in a more homogenous patient population whose clinical scores would change within the typical study period if untreated.

[0223] An additional post-hoc analysis included only subjects with at least one ER mutation.

[0224] Secondary Outcomes: The secondary outcome was responder analysis of Clinical Global Impression-Improvement Scale (CGI-I) scores (responders defined as stable or improved) at 12 months compared to baseline. Other secondary outcomes were responder analysis of 5-domain NPCCSS scores at 12 months compared to baseline (defined as stable or improved), time to deterioration in 5-domain NPCCSS scores (defined as the time until a patient deteriorated by 2 points compared to baseline), proportion of patients with a 2-point deterioration in the 5-domain NPCCSS scores at 6 and 12 months, and change in the 17-domain NPCCSS scores (excluding the hearing domain) at 12 months. Additional secondary outcomes included change from baseline in Scale for Assessment and Rating of Ataxia (SARA) scores at 6 and 12 months, change in 9-Hole Peg Test (9-HPT) results at 6 and 12 months, change in health-related quality of life (HRQoL) measured by the 5-domain 3-level EuroQol questionnaire Young version (EQ-5D-3L Y proxy) at 6 and 12 months, change in individual 5-domain NPCCSS scores at 12 months, and change from baseline in NPC clinical database (NPC-cdb) scores at the time of the study. The NPC-cdb score is intended to reflect clinical status, with an increase in the score indicating a decline in the patient's ability. Scores were calculated according to the definition of Stampfer et al.

[0225] Those skilled in the art will readily appreciate that SARA score, 9-HPT, HRQoL and NPC-cdb are standardized and widely used clinical analysis techniques used to determine the progression of NPC in a subject.

[0226] CGI-I: The CGI-I was originally developed as a research assessment tool to evaluate psychiatric disorders (see Busner and Targum, 2007). It provides the clinician's impression of the improvement (or worsening) of the patient's condition at the current visit compared to baseline on a 7-point scale ranging from 1 (marked improvement) to 7 (marked worse). In this study, the CGI-I was administered after clinical examination and patient interview. The same investigator was instructed to administer the CGI-I assessments throughout the entire study for a given patient.

[0227] SARA: The SARA contains eight items that reflect the neurological symptoms of cerebellar ataxia and provides a direct and simple description of motor function. The total score of the eight items ranges from 0 (normal) to 40 (unable to perform any of the test items) (see Schmitz-Hubsch et al.).

[0228] 9-HPT: The 9-HPT is a direct and brief measure of fine motor coordination, hand / eye coordination, and the ability to follow simple instructions, measured in seconds for each hand. This test is not applicable to children under the age of 4 (see Poole et al.).

[0229] EQ-5D-3L Y proxy version: The HRQoL of study participants was measured using the child version of the EQ-5D-3L Y proxy questionnaire. The questionnaire was completed by the patient's caregiver on behalf of the participant.

[0230] Biomarker quantification: Cholestanetriol, nonesterified cholesterol in serum, and HSP70 levels in peripheral blood mononuclear cells (PBMCs) were measured as described by Mengel et al.

[0231] result Fifty subjects were randomly selected for the study (26 women, 24 men) from 14 centers in nine countries. Thirty-four patients received arimoclomol and 16 received placebo.

[0232] The proportion of patients who completed 12 months of randomized treatment was 79.4% in the arimoclomol group and 93.8% in the placebo group. In the arimoclomol group, reasons for discontinuation included adverse events (n = 3), withdrawal of consent (n = 1), rapid disease progression (early escape clause, n = 2), and death due to NPC progression (n = 1). In the placebo group, one patient withdrew after 1 day due to worsening epilepsy (thought to be part of disease progression).

[0233] The baseline disease characteristics and demographics of the patients are shown in Table 2. [Table 4] TIFF2024502304000009.tif85160

[0234] All subjects were diagnosed with NPC with mutations in both NPC1 alleles. Most patients (n=39 / 50) received miglustat as part of routine clinical care. Baseline mean 5-domain NPCCSS scores, 17-domain NPCCSS scores (excluding the hearing domain), and NPC-cdb scores were higher in the arimoclomol group than in the placebo group (see Table 3). Baseline characteristics of the subgroups are summarized in Table 3. [Table 5] TIFF2024502304000011.tif182160

[0235] All three patients were randomized to the arimoclomol group and had double-function null mutations (see Table 4 ). [Table 6]

[0236] In the case of missense mutations in NPC1, the most common cellular phenotype is retention of misfolded NPC1 protein in the ER, such that the protein does not reach lysosomes. I1061T is the prototype of such ER mutations, and in vitro studies have shown that arimoclomol can increase the amount of properly processed I1061T NPC1 in patient cells (see Example 2). Recent studies have revealed several additional mutations with the same cellular phenotype, including C113R, R389L, G535V, L724P, Q921P, W942C, G1034C, V378A, R404Q, H510P, Q775P, M1142T, N1156S, G1162V, R1186H, L1244P, and I1061T (Shammas et al. 2019, Wang et al. 2020). Two of these, N1156S and R1186H, were also found in this study (see Table 5). The ER subgroup included 11 patients in the arimoclomol treatment group and 4 in the placebo group. [Table 7]

[0237] It is important to note that knowledge of the folding state of most NPC1 missense mutations is limited. Therefore, the ER mutation list contained herein does not constitute a complete list of mutations that may be applied to treatments that enhance the folding and maturation capacity of cells for the NPC1 protein. Indeed, studies have shown that the majority of NPC missense mutations have a misfolding component in their pathogenesis.

[0238] To assess the therapeutic effect of arimoclomol in genetically homogeneous subgroups, patients with at least one known ER missense mutation were identified. Patient demographic characteristics of the ER subgroups are shown in Table 6. [Table 8] TIFF2024502304000015.tif99160

[0239] Efficacy Assessments: For the primary endpoint at 12 months, the mean (95% confidence interval [CI]) change in the 5-domain NPCCSS score was 0.80 (-0.01, 1.60) for arimoclomol compared with 2.14 (1.04, 3.24) for placebo, corresponding to a treatment effect in favor of arimoclomol of -1.34 (95% CI: -2.71, 0.02; p = 0.0537; see Figure 1A) and a 63% relative reduction in annualized disease progression. Patient-level data for change in 5-domain NPCCSS score are shown in Figure 1E.

[0240] First-order multilevel modeling of repeated measures (MMRM) models were applied to predefined subgroup levels that included enough patients to substantiate a formal analysis. In the subgroups of patients aged ≥4 years (n=44, see Figure 1B) and those receiving miglustat concomitantly (n=39, Figure 1C), treatment with arimoclomol resulted in a slower progression of NPC (p<0.05, see Table 7). [Table 9] TIFF2024502304000017.tif186160

[0241] Based on the 5-domain NPCCSS score, the proportion of responders (stable or improved) was 50.0% and 37.5% in the arimoclomol and placebo groups, respectively (see Table 6). At 12 months, the mean differences in the change from baseline in the 17-domain NPCCSS score (excluding the hearing domain) and NPC-cdb score for the arimoclomol vs. placebo groups numerically favored arimoclomol (p=0.5726 and p=0.3785, respectively, see Table 6). For the majority of patients (42 / 50), the study investigators retrospectively completed a baseline CGI-I assessment.

[0242] To determine whether arimoclomol demonstrated specific efficacy within specific subsets of subjects during the study, additional post-hoc analyses based on ASIS and genotype were performed. When patients (n=21) who had a baseline ASIS between 0.5 and 2.0 were analyzed, we observed signal enhancement with a treatment difference of -2.39 in favor of arimoclomol (see Table 7). Furthermore, when patients with null-of-function / null-of-function NPC1 genotypes were excluded from the analysis, there was a dramatic signal enhancement of a treatment effect of -1.56 (see Table 8 and Figure 1D). [Table 10]

[0243] An increase in HSP70 levels was observed in response to 12 months of treatment with arimoclomol (n = 11, mean [standard deviation] change from baseline 1778.98 [1835.56] pg / mL, p = 0.001, see Figure 2A). Nonesterified cholesterol levels in PBMCs increased from baseline to month 12 in both placebo- and arimoclomol-treated patients. Nonesterified cholesterol accumulation was numerically less in arimoclomol-treated patients than in placebo-treated patients (mean treatment difference [standard error (SE)] -44.44 [25.83] μg / mg protein, p = 0.096, see Figure 2B). A numerical decrease in serum cholestanetriol levels was observed in the arimoclomol group compared to the placebo group at 12 months (mean treatment difference [SE] -5.50 [4.46] ng / mL, p = 0.225, see Figure 2C).

[0244] Furthermore, the treatment difference in favor of arimoclomol increased to −4.79 (95% CI, −7.83, −1.74), p = 0.0053) in the subpopulation of patients with ER missense mutations, indicating stronger signal enhancement in this genetically defined group (see Table 9). [Table 11]

[0245] Safety assessments: In total, 88.2% (30 / 34) of patients in the arimoclomol group and 75.0% (12 / 16) in the placebo group had a TEAE. The most common TEAE in both treatment groups was vomiting (arimoclomol: 8 / 34, 23.5%; placebo: 4 / 16, 25.0%). Upper respiratory tract infection and weight loss occurred more frequently with arimoclomol than with placebo, whereas nasopharyngitis, respiratory tract infection, and seizures were reported more often with placebo than with arimoclomol. Serious TEAEs occurred in 14.7% (5 / 34) of patients receiving arimoclomol compared with 31.3% (5 / 16) of patients receiving placebo. All serious TEAEs, except those leading to discontinuation of the study, were considered to be related to NPC. One patient died due to cardiopulmonary arrest that was assessed as related to NPC and not to arimoclomol treatment. Three patients (8.8%) in the arimoclomol group had four TEAEs that led to discontinuation of the study drug. These included two cases of urticaria and one angioedema (both classified as serious and possibly related to the study drug) and one event in which the blood creatinine level rose to twice the patient's baseline value (assessed to be related to the study drug). Six patients in the arimoclomol group had serum creatinine levels rise to more than 1.5 times the patient's baseline value, and in two of these patients (both in the arimoclomol group), the level exceeded twice the baseline value. In one of these patients, the rise occurred during treatment with rescue therapy, and in the other, the rise was reported as a TEAE and the patient discontinued participation in the study as per protocol. No patients had any other signs of affected renal function. In all patients, creatinine levels began to rise at the first measurement after exposure to arimoclomol and peaked before the end of the study. There were no significant changes in vital signs, electrocardiograms, or other laboratory parameters during the study.

[0246] conclusion Without wishing to be bound by theory, the results of the placebo-controlled Phase 2 / 3 12-month trial of arimoclomol in NPC described above indicate that arimoclomol was well tolerated with a clinically meaningful benefit of arimoclomol over placebo observed in test subjects. A significant reduction in disease progression was observed in patients over 4 years of age and in patients co-treated with miglustat. Furthermore, arimoclomol treatment showed increased efficacy in subjects who did not have a functional null / functional null NPC1 genotype (i.e., subjects with either a missense / missense or missense / functional null NPC1 genotype) and in patients from the ER subgroup.

[0247] Example 2 - In vitro testing of cell lines treated with arimoclomol In this experiment, Western blot analysis of PBS- and arimoclomol-treated human fibroblast cell lines harboring missense mutations affecting ER trafficking (GM18453; I1061T / I1061T) and lysosomal localization (GM18420; P1007A / IVS23+4delA) was performed in triplicate to examine the effect of EndoH (endoglycosidase H) deglycosylation treatment on NPC1 protein bands.

[0248] Materials and Methods Cell treatment Fibroblasts were seeded one day (day -1) before treatment with either 400 μM arimoclomol or PBS (control). Cells were treated with arimoclomol continuously from day 0 to day 5, with medium changed on day 3 and harvested on day 5. Thus, cells received 5 days of continuous arimoclomol treatment. Cells were subsequently lysed using RIPA buffer containing protease and phosphatase inhibitors. Protein concentration was quantified for each sample using a BCA assay kit.

[0249] enzymatic digestion Proteins (10 μg protein / sample) were treated with the appropriate enzymes (see Table 10 below and FIG. 5A). Unlike EndoH, which specifically removes glycans from immature proteins in the ER, peptide N-glycosidase F (PNGase) removes all glycans and therefore serves as a digestion positive control. [Table 12]

[0250] SDS-PAGE and Western Blot Proteins were resolved by SDS-PAGE and detected by Western blot (NPC1 & tubulin).

[0251] Image quantification and statistical analysis For quantification of mature and immature forms of NPC1 shown in Figure 5A-B, membranes were imaged and ImageJ software was used to quantify protein bands of immature (EndoH-sensitive) and mature (EndoH-resistant) forms of NPC1 (180-250 kDa) as well as tubulin (50 kDa). NPC1 bands (EndoH-resistant and EndoH-sensitive) were normalized to tubulin. The fold change in EndoH-resistant NPC1 protein after arimoclomol treatment compared to PBS-treated (untreated) controls within each cell line was quantified. Data are presented as mean + / - standard deviation. Statistical significance was performed using paired t-tests (control vs. arimoclomol) for each cell line.

[0252] To determine the abundance of NPC1 protein shown in Figure 4, membranes were imaged and protein bands for NPC1 (180-250 kDa) and tubulin (50 kDa) were quantified using ImageJ software. NPC1 bands were normalized to tubulin or Ponceau staining. The fold change in total NPC1 protein after arimoclomol treatment compared to PBS-treated (untreated) controls within each cell line was quantified. Data are presented as mean + / - standard deviation. Statistical significance was performed using paired t-tests (control vs. arimoclomol) for each cell line. NPC1 genotype for each cell line is shown in Table 11. [Table 13]

[0253] Results and Conclusions Transient expression of tagged NPC1 mutant proteins encoding NPC1 cDNA in mammalian cell lines is frequently used in combination with the endoglycosidase H (EndoH) enzyme, which digests immature glycosylated structures specifically on ER-retained proteins, as a system to model trafficking from the ER. In these experimental conditions, nearly all I1061T NPC1 proteins were sensitive to EndoH, indicating a strong block to budding from the ER, and several other mutations found in this study have been shown to have similar phenotypes (Shammas et al. 2019).

[0254] Treatment of NPC patient fibroblasts harboring the ER mutation (I1061T / I1061T) with arimoclomol induced a time- and dose-dependent increase in the expression of HSPA1A, the gene encoding HSP70, after 5 days compared with phosphate-buffered saline (PBS)-treated controls (see Figure 3).

[0255] Treatment with arimoclomol increased the total amount of NPC1 protein in patient fibroblasts harboring the most common mutations in NPC1 compared to PBS-treated controls (see Figure 4).

[0256] Arimoclomol increased the amount of properly processed NPC1 protein, as quantified by the amount of EndoH-resistant NPC1, in NPC fibroblasts harboring a missense mutation affecting ER trafficking (I1061T; GM18453) and a missense mutation affecting lysosomal localization (P1007A; GM18420), compared with PBS-treated cells (see Figure 5A).

[0257] EndoH specifically removes glycans from immature proteins in the ER, allowing differentiation between immature (sensitive) and mature (resistant) forms of NPC1. Treatment with arimoclomol increased the amount of properly processed NPC1 protein, as quantified by the amount of EndoH-resistant NPC1, in NPC fibroblasts harboring a missense mutation affecting ER trafficking (I1061T; GM18453) and a missense mutation affecting lysosomal localization (P1007A; GM18420), compared to PBS-treated cells (Figure 5B).

[0258] Mutations in GM18453 result in NPC1 protein that is misfolded and retained in the endoplasmic reticulum (ER), where it is subsequently targeted for degradation. Importantly, HSP70 has been shown to directly bind to I1061T NPC1 and aid in the proper folding and maturation of the protein. These data demonstrate that treatment of patient fibroblasts carrying ER missense mutations with arimoclomol results in a clear increase in properly matured NPC1 protein.

[0259] Thus, patients harboring at least one ER mutation are expected to benefit from both the beneficial effects of arimoclomol on lysosomal homeostasis and heat shock protein (HSP)-dependent refolding, as well as maturation of ER-retained misfolded NPC1.

[0260] References Busner and Targum.“The clinical global impressions scale: applying a research tool in clinical practice”.Psychiatry(Edgmont). 2007;4:28-37 Cortina-Borja et al.”Annual severity increment score as a tool for stratifying patients with Niemann-Pick disease type C and for recruitment to clinical trials.”Orphanet J Rare Dis,2018;13(1):143;3 Imrie et al.2007.“The Natural History of Niemann-Pick Disease Type C in the UK.”Journal of Inherited Metabolic Disease30(1):51-59.https: / / doi.org / 10.1007 / s10545-006-0384-7. Gelsthorpe et al.2008.“Niemann-Pick Type C1 I1061T Mutant Encodes a Functional Protein That Is Selected for Endoplasmic Reticulum-Associated Degradation Due to Protein Misfolding.”The Journal of Biological Chemistry283(13):8229-36. Mengel et al.”Clinical disease progression and biomarkers in Niemann-Pick disease type C:a prospective cohort study.”Orphanet J Rare Dis.2020;15:328 Poole et al.“Measuring dexterity in children using the Nine-hole Peg Test”.J Hand Ther.2005;18:348-51 Schmitz-Hubsch et al.“Scale for the assessment and rating of ataxia: development of a new clinical scale”.Neurology.2006;66:1717-20 Schultz et al.2018.“Coordinate Regulation of Mutant NPC1 Degradation by Selective ER Autophagy and MARCH6-Dependent ERAD.”Nature Communications9(1):3671. Shammas et al.2019.“Different Niemann-Pick C1 Genotypes Generate Protein Phenotypes That Vary in Their Intracellular Processing,Trafficking and Localization.”Scientific Reports9(1):5292. Stampfer et al.“Niemann-Pick disease type C clinical database:cognitive and coordination deficits are early disease indicators.”Orphanet J Rare Dis.2013;8:35doi:10.1186 / 750-72-8-35 Wang et al.“Individualized management of genetic diversity in Niemann-Pick C1 through modulation of the Hsp70 chaperone system.”Human molecular genetics vol.29,1(2020): 1-19.doi:10.1093 / hmg / ddz215 Yanjanin et al.”Linear Clinical Progression,Independent of Age of Onset,in Niemann-Pick Disease,type C.”Am J Med Genet B Neuropsychiatr Genet,2010;153B(1):132-140

Claims

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 treating or preventing Niemann-Pick disease type C (NPC) in a subject, wherein the subject has an endoplasmic reticulum (ER)-type missense mutation in the NPC gene.

2. 2. The active pharmaceutical ingredient for use according to claim 1, wherein the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride and acid addition salts thereof, for example the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate (arimoclomol).

3. The active pharmaceutical ingredient for use according to any one of claims 1 to 2, wherein the treatment or prevention further comprises administering a further active pharmaceutical ingredient selected from N-alkyl derivatives of 1,5-dideoxy-1,5-imino-D-glucitol, wherein the alkyl contains 2 to 8 carbon atoms, its stereoisomers and its acid addition salts, e.g. the further active pharmaceutical ingredient is N-butyl-deoxynojirimycin (miglustat).

4. The active pharmaceutical ingredient for use according to any one of claims 1 to 3, wherein the NPC gene is selected from NPC1 and NPC2, for example the NPC gene is NPC1.

5. An active pharmaceutical ingredient for use according to any one of claims 1 to 4, wherein the ER-type missense mutation in the NPC gene results in production of an NPC protein that is misfolded, retained in the endoplasmic reticulum (ER) and subsequently targeted for degradation, wherein the NPC protein is selected from NPC1 and NPC2, for example the NPC protein is NPC1.

6. 6. The active pharmaceutical ingredient for use according to any one of claims 1 to 5, wherein the ER-type missense mutation is selected from the group consisting of C113R, R389L, G535V, L724P, Q921P, W942C, G1034C, V378A, R404Q, H510P, Q775P, M1142T, N1156S, G1162V, R1186H, L1244P and I1061T.

7. The subject is I1061T / E1188 ＊ 7. The active pharmaceutical ingredient for use according to any one of claims 1 to 6, wherein the active pharmaceutical ingredient has an NPC1 genotype selected from the group consisting of: I1061T / A1151T, I1061T / Q119fs, I1061T / I962fs, T1036M / I1061T, I1061T / V1141G, N968S / R1186H, N1156S / F1199sp2, Q991fs / I1061T, H1016L / I1061T, I1061T / A1192fs, I1061T / N1156S, R1186H / R1186H, P1007A / R1186H, and I1061T / D508fs.

8. 8. The active pharmaceutical ingredient for use according to any one of claims 1 to 7, wherein administration of said active pharmaceutical ingredient provides sustained benefit over a period of 2 years.

9. The active pharmaceutical ingredient for use according to any one of claims 1 to 8, wherein the subject is about 4 years of age or older.

10. 10. The active pharmaceutical ingredient for use according to any one of claims 1 to 9, wherein the active pharmaceutical ingredient is administered at 100 mg / day to 1000 mg / day, e.g. the active pharmaceutical ingredient is (+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate and is administered at 100 mg / day to 1000 mg / day, e.g. the active pharmaceutical ingredient is administered three times daily (t.i.d.).

11. 11. The active pharmaceutical ingredient for use according to any one of claims 1 to 10, wherein the active pharmaceutical ingredient is administered at 150 mg / day, such as 225 mg / day, for example 300 mg / day, such as 450 mg / day, or such as 600 mg / day ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate), e.g. wherein the active pharmaceutical ingredient is administered three times daily (t.i.d.).

12. the subject has a body weight between 8 kg and 15 kg, and the active pharmaceutical ingredient is administered at a dose of 50 mg t.i.d. (150 mg / day) ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate); For example, the subject has a body weight between 8 kg and 15 kg, and the active pharmaceutical ingredient is administered at a dose of 75 mg t.i.d. (225 mg / day) ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate); For example, the subject has a body weight between 15 kg and 22 kg, and the active pharmaceutical ingredient is administered at a dose of 75 mg t.i.d. (225 mg / day) ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate); For example, the subject has a body weight between 22 kg and 38 kg, and the active pharmaceutical ingredient is administered at a dose of 100 mg t.i.d. (300 mg / day) ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate); For example, the subject has a body weight between 38 kg and 55 kg, and the active pharmaceutical ingredient is administered at a dose of 150 mg t.i.d. (450 mg / day) ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate); For example, the subject has a body weight between 15 kg and 30 kg, and the active pharmaceutical ingredient is administered at a dose of 100 mg t.i.d. (300 mg / day) ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate); For example, the subject has a body weight between 30 kg and 55 kg, and the active pharmaceutical ingredient is administered at a dose of 150 mg t.i.d. (450 mg / day) ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate); 12. The active pharmaceutical ingredient for use according to any one of claims 1 to 11, for example, wherein the subject has a body weight of more than 55 kg and the active pharmaceutical ingredient is administered at a dose of 200 mg t.i.d. (600 mg / day) ((+)-(R)-N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride citrate).

13. 1. A method for predicting responsiveness of a subject suffering from Niemann-Pick disease type C (NPC) to treatment with arimoclomol or a combination of arimoclomol and miglustat, comprising: a) determining whether the subject has an ER-type missense mutation in an NPC gene, e.g., in the NPC1 gene; b) predicting that the subject will respond to treatment with arimoclomol or a combination of arimoclomol and miglustat if the subject is determined to have an ER-type missense mutation in an NPC gene, e.g., in the NPC1 gene; Including, c) optionally the method comprises one or more steps of administering arimoclomol, or one or more steps of administering arimoclomol and miglustat; method.

14. 1. A method for identifying a subject suffering from Niemann-Pick disease type C (NPC) likely to be responsive to treatment with arimoclomol or a combination of arimoclomol and miglustat, comprising: a) determining whether the subject has an ER-type missense mutation in an NPC gene, e.g., in the NPC1 gene; b) identifying the subject as likely to respond to treatment with arimoclomol or a combination of arimoclomol and miglustat if the subject is determined to have an ER-type missense mutation in an NPC gene, e.g., in the NPC1 gene; Including, c) optionally the method comprises one or more steps of administering arimoclomol, or one or more steps of administering arimoclomol and miglustat; method.

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