Aprelomol compositions for treatment of Niemann-Pickk Disease Type C (NPC)

Abstract

The present invention relates to a pharmaceutical composition or formulation of an aprenomol citrate salt, which is a monodrug therapy or a combination therapy therapy with megranurite, for use in one or more methods of treating Niemann-Picker Disease Type C (NPC) in a human patient. The present invention also relates to aprenomol for use in a method of treating NPC in a human patient by dispersing or suspending a pharmaceutical composition comprising a formulation of aprenomol, in particular aprenomol citrate, in at least one liquid or at least one solid medium, and then administering to the patient. The present disclosure also relates to biomarkers and metabolites of aprenomol.

Description

[0001] Statement of Related Applications

[0002] This application is a conversion of U.S. Provisional Patent Application 63 / 419,985, filed October 27, 2022, and claims the priority of that date, and all of its materials are incorporated herein by reference. Background of the Invention

[0004] Niemann-Pick disease type C (NPC) is a rare, progressive, and fatal neurodegenerative disorder with an estimated incidence of ~1:100,000 live births (Geberhiwot et al. 2018). It is characterized by a progressive loss of function, which usually leads to death before adulthood. Overall, the average life expectancy of patients with NPC is 13 years (Bianconi et al. 2019). It has a significant impact on all aspects of the lives of patients and their families.

[0005] The disease is characterized by a series of progressive and disabling symptoms, including increasing difficulty with basic functions such as walking, motor coordination, swallowing, speaking, concentration, and memory, leading to complete dependence on family and caregivers.

[0006] NPC is an autosomal recessive disorder caused by mutations in the NPC1 (95% of cases) or NPC2 gene. Both genes encode lysosomal proteins that are essential for the intracellular trafficking and metabolism of lipids. Due to the mutations, NPC proteins are often misfolded and prematurely degraded, resulting in dysfunction of one or both of the NPC proteins. Due to the dysfunction of either of these NPC proteins, lysosomal function is impaired, leading to the accumulation of lipids in lysosomes, which in turn causes cellular stress and toxicity (Lloyd-Evans and Platt 2010; Platt et al. 2018). Over time, this leads to neurodegeneration and peripheral organ dysfunction. The liver, spleen, and lungs may also be affected. The age of onset of NPC disease can vary widely, from a rapidly progressive and fatal disorder in neonates to a slowly progressive neurodegenerative disease with adult onset.

[0007] The disease is characterized by a series of progressive and disabling symptoms, including increasing difficulty with basic functions such as walking, motor coordination, swallowing, speaking, concentration, and memory, leading to complete dependence on family and caregivers (Wraith and Imrie 2007). The progressive decline in brain function leads to a significant decrease in the quality of life of patients and their families (Benussi et al. 2018).

[0008] Although most often manifested during childhood and adolescence, NPC can occur at any stage of life, has highly diverse symptoms, and has variable rates and patterns of progression—ranging from a rapidly progressive and fatal disorder in neonates, to a slowly progressive neurodegenerative disease with adult onset. NPC can be classified by the age of onset of neurological symptoms: early infancy (onset before 2 years of age), late infancy (onset between 2 and 6 years of age), juvenile (onset between 6 and 15 years of age), and adult (onset after 15 years of age). Disease progression is strongly associated with the age of onset of neurological symptoms. An early age of onset of neurological signs and symptoms also predicts rapid disease progression. The bifunctional null NPC1 genotype predicts early infancy and severe NPC. No single symptom can predict the rate of progression in an individual patient (Vanier 2010; Yanjanin et al. 2010).

[0009] Systemic signs of liver, spleen, and lung involvement usually precede the neurodegeneration that defines the disease. This is especially true for patients with onset during infancy and childhood. Neurological signs and symptoms include difficulty walking and gait, cognitive impairment, dysphagia, vertical supranuclear gaze palsy, epilepsy, and ataplexy. Progression of neurological symptoms is, in most cases, the cause of disability and premature death (Vanier 2010).

[0010] The high variability of most signs and symptoms of NPC, combined with little or no experience with the disease among clinicians, results in substantial diagnostic delays, misdiagnoses, and delayed interventions. However, in the case of a child in whom the disease has been confirmed, siblings can be diagnosed with NPC by genetic testing before the onset of any visible signs or symptoms.

[0011] In the terminal stage, the patient is bedridden, with complete ophthalmoplegia, and loss of intentional movement due to severe encephalopathy, with uncontrolled epilepsy. At this stage, treatment consists mainly of palliative care.

[0012] Although miglustat is approved in the European Union (EU) for the treatment of the progressive neurological manifestations in patients with NPC, there is currently no cure or disease-modifying therapy for NPC. Thus, there is a high unmet medical need for new treatment options (Geberhiwot et al. 2018). Given the progressive, debilitating, life-limiting, and fatal nature of NPC disease (i.e., high morbidity), there is an urgent need for therapies that delay disease progression, as patients continue to experience progressive neurodegeneration with a fatal outcome. In a recent paper, 338 deaths due to NPC were described over a 50-year observation period, with a mean age of 13 years, and it was concluded that there has been no significant change in survival over the past 20 years (Bianconi et al. 2019).

[0013] Since there is no cure or disease-modifying therapy for NPC, and thus there is a high unmet medical need for new treatment options (Geberhiwot et al. 2018). Given the progressive, debilitating, life-limiting, and fatal nature of NPC disease (i.e., high morbidity), there is an urgent need for therapies that delay disease progression, such as the monotherapy or combination therapy with miglustat of arimoclomol citrate of the present disclosure. There is also a need to provide improved delivery and administration of arimoclomol drugs to improve patient compliance with such administration, especially in the case of patients aged 2 years or younger.

[0014] Summary of the Invention

[0015] The present disclosure also relates to a method of treating NPC in a human patient, the method comprising a pharmaceutical composition or formulation of arimoclomol citrate or a pharmaceutically acceptable salt thereof, which is a monotherapy or a combination therapy with miglustat. The present disclosure also relates to a method of treating NPC in a human patient by dispersing or suspending a pharmaceutical composition comprising a formulation of arimoclomol, particularly arimoclomol citrate, in at least one liquid or at least one solid medium and then administering it to the patient. The present disclosure also relates to biomarkers and metabolites of arimoclomol.

[0016] Is an arimoclomol citrate formulation suitable for the treatment of Niemann-Pick disease type C (NPC) in patients aged 2 years and older, in combination with miglustat and as monotherapy in patients not suitable for treatment with miglustat.

[0017] In at least one aspect of the present disclosure, the present disclosure provides a method for treating Niemann-Pick disease type C (NPC) in a human patient in need thereof, the method comprising the steps of: providing to the patient a pharmaceutical composition or formulation of an amount of arilomol or a pharmaceutically acceptable salt thereof; wherein the composition or formulation of arilomol is provided in a capsule dosage form; and wherein the pharmaceutical composition or formulation of an amount of arilomol or a pharmaceutically acceptable salt thereof is selected from the group consisting of 31 mg, 47 mg, 62 mg, 93 mg, and 124 mg of arilomol (in base form); opening the capsule dosage form and dispersing the pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof in at least one liquid or at least one solid medium to form at least one dispersion; wherein the liquid medium is a member of the group consisting of at least one selected from water and apple juice; wherein the solid medium is selected from the group consisting of at least one soft food; and administering the dispersion to the patient within a twenty-four period of time after the pharmaceutical composition or formulation or a pharmaceutically acceptable salt thereof is dispersed in at least one liquid or solid medium.

[0018] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0019] Figure 1 is a chemical diagram showing the metabolism of arilomol.

[0020] Figure 2 is Table 41, titled Comparison of Test Data Obtained from Containers 1-6 and Containers 7-12.

[0021] Figure 3 is titled Figure 2-3 , depicting a graph showing the mean plasma concentrations of arilomol and its metabolites M2, M5, and M105 after multiple doses of 248 mg three times a day (t.i.d.) - Trial OR-ARI-MET-01.

[0022] Figure 4 is Table 2-5, titled Single and Multiple Dose Pharmacokinetic Parameters of Arilomol Metabolites M2, M5, and M105 in Male Subjects - Trial OR-ARI-MET-01.

[0023] Figure 5 is Table 11-2, titled Summary Statistics of Plasma Pharmacokinetic Parameters of M2 after Treatment Doses (200 mg) of Arilomol TID (Treatment A) on Day 1 and Day 3.

[0024] Figure 6 is Table 11-5, titled Summary Statistics of Plasma Pharmacokinetic Parameters of M2 after Supra-Treatment Doses (600 mg) of Arilomol TID (Treatment B) on Day 1 and Day 3.

[0025] Figure 7 Table 11-3, titled Summary Statistics of Plasma Pharmacokinetic Parameters of M105 after Treatment Dose (200 mg) of Arerolimod TID (Treatment A) on Day 1 and Day 3.

[0026] Figure 8 Table 11-6, titled Summary Statistics of Plasma Pharmacokinetic Parameters of M2 after Supra-Treatment Dose (600 mg) of Arerolimod TID (Treatment B) on Day 1 and Day 3.

[0027] Figure 9 Table 3-4, titled Dose Proportionality of Arerolimod after Multiple t.i.d. Administrations.

[0028] Figure 10 Table 3-3, titled Oral Clearance of Arerolimod after Single and Multiple t.i.d. Oral Administrations of 31 to 372 mg.

[0029] Figure 11 Table 2-10, titled Summary Statistics of Arerolimod Exposure Variables Stratified by Body Weight.

[0030] Figure 12 is titled Figure 3-6 , and depicts a tabular comparison showing the effect of liver impairment on the single-dose pharmacokinetics of Arerolimod - Trial OR-ARI-HEP-01.

[0031] Figure 13 Table 6-6, and is titled Intrinsic Factor Pharmacokinetic Trials and Resulting AUC and Cmax for a 248 mg Dose for Various Liver Conditions.

[0032] Figure 14 is titled Figure 3-4 , and shows the effect of age, sex, and weight on the multiple-dose pharmacokinetics of Arerolimod - Population Pharmacokinetic Analysis in Adults, Cmax (top) AUC0-8 (bottom).

[0033] Figure 15 is a graph showing the estimated change from baseline to month 36 in the 5-domain NPCCSS of double-blind and open-label Arerolimod.

[0034] Figure 16 is a tabular comparison showing the p-values of Arerolimod relative to placebo for the overall population and the subgroup using miglustat at baseline.

[0035] Figure 17 is titled Figure 2-17and depicts an analysis of the change from baseline to month 12 in the 5 - domain and full - scale NPCCSS in subgroups based on age at first neurological symptom (FAS). DETAILED DESCRIPTION OF THE INVENTION

[0037] The present disclosure relates to a method of treating NPC in a human patient or patients, the method comprising a pharmaceutical composition or formulation of arimoclomol citrate or a pharmaceutically acceptable salt thereof, which is a monotherapy or a combination therapy with miglustat. The present disclosure also relates to a method of treating NPC in a human patient by dispersing or suspending a pharmaceutical composition of a formulation of arimoclomol, particularly arimoclomol citrate, in at least one liquid or at least one solid medium and then administering it to the patient. The present disclosure also relates to biomarkers and metabolites of arimoclomol.

[0038] Arimoclomol citrate capsules are provided in five specifications expressed as arimoclomol base: 31 mg, 47 mg, 62 mg, 93 mg, and 124 mg. It is easily administered to patients with dysphagia, including pediatric patients, because it is formulated in capsules that can be opened and the contents can be dispersed in a liquid (such as but not limited to apple juice or a similar beverage) or a soft food (e.g., applesauce, gelatin, baby food, etc., which are used for neonates, pediatric, and other patients in need of such a soft medium) without any significant or potentially significant loss of potency for at least 24 hours. In one embodiment of the present disclosure, the contents of the arimoclomol citrate capsules can be easily suspended in 20 mL of water for administration via a feeding tube, or alternatively, can be sprinkled on soft foods and beverages with different textures, viscosities, and pHs without any loss of potency for at least 24 hours.

[0039] Arimoclomol citrate (N - [(2R,Z)-2 - hydroxy - 3-(1 - piperidinyl)propoxy]pyridine - 3 - carboximidoyl chloride, 1 - oxide, citrate) is a synthetic chemical entity also known as BRX - 345. Arimoclomol is a heat - shock protein amplifier.

[0040] In at least one embodiment of the present disclosure, a method of treating NPC in a patient is provided, wherein the treatment comprises administering arimoclomol citrate to a patient in need thereof. In one or more alternative embodiments, the patient in need is 2 years of age or older, or alternatively 2 years of age or younger. In another embodiment, the treatment is a monotherapy with arimoclomol only (e.g., ) especially where the patient is not suitable for treatment with miglustat. In another embodiment, the treatment further comprises administering miglustat to a patient in need thereof.

[0041] In additional embodiments of the present disclosure, methods of treating NPC in a patient are provided, wherein the treatment comprises administering arilomol citrate to a patient in need thereof, wherein the dose is selected from the group consisting of 31 mg, 47 mg, 62 mg, 93 mg, and 124 mg of arilomol (base). In alternative embodiments, the patient in need is 2 years of age or older, or alternatively 2 years of age or younger. In another embodiment, the treatment is a monotherapy with arilomol only and in particular wherein the patient is not suitable for treatment with miglustat. In another embodiment, the treatment further comprises administering miglustat to a patient in need thereof.

[0042] In additional embodiments of the present disclosure, methods of treating NPC in a patient are provided, wherein the treatment comprises administering arilomol citrate to a patient in need thereof, wherein the administration can be oral, such as via a capsule, or the capsule can be opened and dispersed in a liquid (such as a suspension) or a soft food (such as applesauce, gelatin, baby food, etc., which are used for neonates, pediatric, and other patients in need of such a soft medium). In alternative embodiments, the patient in need is 2 years of age or older, or alternatively 2 years of age or younger. In another embodiment, the treatment is a monotherapy with arilomol only and in particular wherein the patient is not suitable for treatment with miglustat. In another embodiment, the treatment further comprises administering miglustat to a patient in need thereof.

[0043] In another embodiment of the present disclosure, one or more metabolites of arilomol citrate are provided. In one embodiment, the one or more metabolites are selected from the group consisting of M2, M5, and M105.

[0044] In one embodiment, the present disclosure relates to the use of arilomol citrate for the treatment of Niemann-Pick disease type C (NPC) in patients 2 years of age and older, or alternatively 2 years of age or younger, as a monotherapy or as combination therapy with miglustat.

[0045] In alternative embodiments, (an arilomol citrate preparation) is suitable for the treatment of Niemann-Pick disease type C (NPC) in patients 2 years of age and older, in combination with miglustat or as a monotherapy in patients not suitable for treatment with miglustat.

[0046] Mode of action

[0047] Not wishing to be bound by a particular concept, arimoclomol is considered an orally available small molecule that crosses the blood-brain barrier (BBB) (Cudkowicz et al. 2008). Arimoclomol amplifies and maintains the cellular production of heat shock proteins (HSPs), particularly HSP70, by prolonging the activation of heat shock factor-1 (HSF-1) and inducing the HSR (Kalmar et al. 2008; Neef, Jaeger, and Thiele 2011). HSP70 and other HSPs are essential for the correct folding and processing of the lysosomal membrane protein NPC1, including misfolded mutants, which are the most common form of mutant NPC1 in patients with NPC (Nakasone et al. 2014; Millat et al. 2001). The HSR is directly related to lysosomal integrity through HSP70-mediated stabilization of the lysosomal membrane and protection from cell death (Kirkegaard et al. 2010; Petersen et al. 2010; Nylandsted et al. 2004). Thus, by amplifying the HSR, arimoclomol targets both protein misfolding and lysosomal dysfunction through the natural cellular defense mechanism. Therefore, arimoclomol has a new mechanism of action that targets the root cause of the NPC etiology: NPC protein misfolding and lysosomal dysfunction (Ingemann and Kirkegaard 2014; Neef, Jaeger, and Thiele 2011; Kirkegaard et al. 2016).

[0048] In one embodiment of the present disclosure, the finished product is provided as a hard capsule containing 31, 47, 62, 93, or 124 mg of arimoclomol citrate as the active substance (base), respectively. In one embodiment, other inert ingredients may include microcrystalline cellulose and magnesium stearate (as part of the capsule contents).

[0049] In one embodiment of the present disclosure, arimoclomol citrate Capsule shell:

[0050] 31 mg: hypromellose, titanium dioxide, brilliant blue FCF - FD&C Blue 1;

[0051] 47 mg: hypromellose, titanium dioxide, brilliant blue FCF - FD&C Blue 1, yellow iron oxide;

[0052] 62 mg: hypromellose, titanium dioxide, yellow iron oxide;

[0053] 93 mg: hypromellose, titanium dioxide, yellow iron oxide, red iron oxide;

[0054] 124 mg: Hypromellose, Titanium Dioxide, Red Iron Oxide.

[0055] Printing Ink: Shellac, Black Iron Oxide, Propylene Glycol, Ammonia, Potassium Hydroxide.

[0056] Active Substance

[0057] Arilomol is a chiral molecule which contains one chiral center (R-enantiomeric form) and is provided as a white to off-white crystalline powder. Arilomol citrate (N-[(2R,Z)-2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-3-carboximidoyl chloride, 1-oxide, citrate) is a synthetic chemical entity. It should be emphasized that it is slightly hygroscopic, presents as the R-enantiomeric form, and is always observed as polymorph 1.

[0058] Pharmacology

[0059] Niemann-Pick disease type C (NPC) belongs to the larger group of diseases known as lysosomal storage disorders (Platt et al., 2018). NPC is a rare progressive autosomal recessive disorder characterized by the body's inability to transport cholesterol and other sphingolipids within cells. NPC is caused by mutations in either the NPC1 gene (NPC type 1C, 95%) or the NPC2 gene (NPC type 2C, 5%), both of which are lipid transport proteins located in lysosomes. Due to this genetic disorder, abnormal accumulation of lipids is observed in lysosomes and retention of mutant NPC1 protein is observed in the endoplasmic reticulum. These accumulations lead to enhanced degenerative processes such as autophagy and cell death. Patients mainly suffer from these degenerative processes in the central nervous system, liver, spleen, and lungs.

[0060] Arilomol is an orally available small molecule intended for administration to NPC patients aged 2 years and older, or alternatively aged 2 years or younger. Depending on the age and weight of the patient, the recommended dose of arilomol (arilomol base, arilomol citrate) ranges from 31 mg to 124 mg and should be given three times daily with or without food.

[0061] Without wishing to be bound by any particular theory, the rationale for arilomol administration is based on the following observations: enhanced expression of the transcription factor HSF1, leading to induction of the heat shock response (HSR), HSP70, and mature NPC1 protein. Therefore, administration of arilomol should result in stabilization of lysosomal integrity and restoration of misfolded NPC1 mutations in Niemann-Pick type C disease.

[0062] The exact targeting mechanism of arilomol is unknown. However, administration of up to 400 μM arilomol significantly increased HSF1, HSP70, and NPC1 cholesterol transporter in human fibroblasts from NPC1 patients (but not below 100 μM). Collectively, a concentration of 400 μM arilomol was considered to significantly enhance the heat shock response and the processing of mature glycosylated NPC1 protein.

[0063] The three most abundant arilomol metabolites (M2, M5, and M105) in humans at steady state were ineffective in inducing HSP70 and increasing NPC1 protein levels in human fibroblasts from NPC1 patients.

[0064] In vivo studies of arilomol were also conducted in NPC− / − mouse models. This animal model mimics the lesions of NPC disease and is therefore considered suitable for evaluating the efficacy of arilomol. Importantly, 30 mg / kg arilomol significantly increased the overall survival of NPC− / − mice (Kirkegaard et al. 2016). Arilomol was administered orally at daily doses of 1–300 mg / kg (Kirkegaard et al. 2016; study no. CRO-1211210031). Although the data within the publication by Kirkegaard et al. were consistent, this was not the case if the data from study no. CRO-1211210031 were included (Kirkegaard et al. 2016).

[0065] Although not wishing to be bound by any particular theory, the effect of arilomol on Npc1− / − mice provides evidence that arilomol targets the etiology of NPC. Arilomol (oral 10 mg / kg) significantly activated HSF1 and increased HSP70 protein levels in the brain but not in liver tissue of Npc1− / − mice, probably due to differences in the expression and nuclear turnover of HSF1 in this tissue.

[0066] Arilomol was shown to improve gait parameters in the absence of NPC1 protein. This suggests that arilomol activates HSF1 and increases the levels of HSP70, which in turn improves lysosomal function within the CNS, reduces lipid deposition, and improves myelination and preservation of cerebellar architecture. This provides an alternative mechanism of action for arilomol in the absence of NPC1 protein and supports the improved motor outcomes in mice.

[0067] Pharmacokinetics

[0068] Study 7027-130 was conducted to determine whether human cytochrome P450 isozymes are involved in the in vitro metabolism of radiolabeled arelomol in human microsomes (using NADPH as cofactor). The in vivo metabolism (as well as absorption and excretion) of radiolabeled arelomol was then studied in intact and bile duct-cannulated male rats, 6 to 9 weeks of age, after oral administration (375 mg / kg salt) (Study 7027-122). Similarly, the absorption, metabolism, and excretion of radiolabeled arelomol were studied in intact and bile duct-cannulated female and male beagle dogs after oral administration (70 mg / kg) (Study 7027-124). Then, in an earlier study, BRX-345PRE SK-006, metabolites from rat and human samples were identified and characterized based on liquid chromatography separation coupled with mass spectrometry (MS). In a later study, Part 2 of 287N-0801, metabolites were identified and profiled in plasma, urine, and feces after oral administration of radiolabeled arelomol (2500 mg / kg) to male CD-1 mice (samples were collected from Part 1 of Study 287N-0801). Subsequently, in Study XT194101, the applicant investigated which (recombinant) UDP-glucuronosyltransferases were involved in the in vitro turnover of arelomol to the glucuronide conjugate metabolite M5 in human microsomes. In Study XT194103, the applicant attempted to investigate the metabolic pathway for the conversion of arelomol to the important cleavage product metabolite M105 in human microsomes (using NADPH as cofactor), with particular emphasis on the role of (recombinant) flavin-containing monooxygenase (FMO). Subsequently, in Study 8384372, the absorption and metabolism of radiolabeled arelomol (375 mg / kg) were studied in male rats after oral gavage administration. In addition, the metabolism and disposition of arelomol-related substances in plasma were evaluated in this study after repeated-dose administration (for 28 days, samples were obtained from a rat fertility study, 8376167). In addition, a human metabolism study was submitted in this dossier. In Study 8393986, the applicant characterized the plasma metabolites of arelomol after repeated administration for up to six days (at 400 mg, three times daily, with an 8-h dosing interval) at steady state (samples were obtained from clinical study 180308-CS030, sponsor reference number: OR ARI-MET-01). In data report 8412783, additional data from Study 8393986 were provided.

[0069] The CYP450 monooxygenases are inefficient in the phase I metabolism of arelomol, with only the isoforms 1A2 and, to a lesser extent, 2D6 showing metabolism of arelomol, but CYP450-mediated metabolism is quantitatively negligible compared to other turnover pathways. Arelomol is metabolized via multiple pathways, as shown below Figure 1 as follows:

[0070] The major pathways of arecolomine metabolism are as follows: a.) dechlorination, followed by glutathione conjugation and derivatization of the conjugate moiety; b.) O-glucuronidation; and c.) NO cleavage. In animals and humans, the most abundant metabolites produced by these reactions at steady state are M2 (cysteine conjugate), M5 (O-glucuronide), and M105 (cleavage product). The applicant demonstrated that different UDP-glucuronosyltransferase isotypes (notably UGT1A3, 1A9, 2B4, 2B7, and 2B17) can convert arecolomine to M5 in human microsomes in vitro. The exact molecular mechanism behind NO cleavage has not been determined; however, FMO1 and FMO3 were demonstrated in vitro to potentially form M105 from intermediate 104 (and M109 from arecolomine). However, the applicant did not succeed in elucidating the metabolic pathway that gives rise to M104. Metabolism is very similar between the non-clinical species and humans tested. During non-clinical animal studies, the major metabolites in human plasma (>10%: M2, M5, and M105) were present in sufficient amounts; therefore, their safety profiles can be considered acceptable.

[0071] As previously discussed, the profile of arecolomine-related substances in plasma is different after chronic administration compared to after single administration, whereby the fraction of arecolomine metabolites in the total plasma amount of arecolomine-related substances increases substantially after chronic administration (because of their slower elimination kinetics).

[0072] Bioanalytical methods

[0073] Bioequivalence

[0074] A BCS-based biowaiver is requested to establish bioequivalence between the early clinical trial product and the product to be marketed.

[0075] For the blinded phase of clinical trial 2 / 3 CT-ORZY-NPC-002, in order to ensure blinding, a capsule formulation with an excess of excipient material for the lower capsule strength was required. Then, between the blinded and open-label (OL) phases of the CT-ORZY-NPC-002 trial, the capsule formulation was changed to optimize it for patients by reducing the capsule fill weight and the amount of excipient taken with each capsule. In addition, the gelatin capsule shell was replaced with a shell of hydroxypropyl methylcellulose (HPMC).

[0076] Dissolution studies of P741 arecolomine citrate capsules under 3 different pH conditions support the biowaiver.

[0077] Dissolution testing was performed in apparatus 2 at 75 rpm using 900 mL of the following dissolution media:

[0078] -(1) Hydrochloric acid medium, pH 1.2;

[0079] -(2) Acetate buffer solution, pH 4.5;

[0080] -(3) Phosphate buffer solution, pH 6.8.

[0081] Twelve dosage units of each strength of the test drug and reference drug were evaluated in two separate sequences (six capsules per sequence). Samples were collected at time points of 5, 10, 15, 20, 30, 45, and 60 minutes to characterize the complete dissolution profile of the drug product.

[0082] - Batch 8211X (124 mg validation batch) - Test product formulation

[0083] - Batch 8602X (93 mg validation batch) - Test product formulation

[0084] - Batch 8106X (62 mg validation batch) - Test product formulation

[0085] - Batch 8502X (47 mg validation batch) - Test product formulation

[0086] - Batch 8404X (31 mg validation batch) - Test product formulation

[0087] - Batch 16E03C (31 mg CTM batch) - Reference product formulation

[0088] - Batch 16F07C (62 mg CTM batch) - Reference product formulation

[0089] Results

[0090] For the reference product, both the 31 mg and 62 mg dosage strengths clearly showed very rapid dissolution characteristics.

[0091] For the test product, the 31 mg, 47 mg, and 124 mg capsule strengths dissolved 85% or more of the drug label claim on average within 15 minutes in all three dissolution media.

[0092] For the 62 mg dosage strength of the test product, 85% or more of the drug label claim dissolved within 15 minutes at pH 1.2 and 4.5. However, at pH 6.8, 84% of the label claim dissolved at 15 minutes.

[0093] Similarly, for the 93 mg dosage strength, at pH 4.5 and 6.8, an average of 85% or more of the drug label claim is dissolved within 15 minutes, but at pH 1.2, an average of 84% of the label claim is dissolved at 15 minutes.

[0094] The results of the test product batches for the 62 mg and 93 mg dosage strengths were analyzed, which failed to meet the criteria of ≥ 85% dissolution within 15 minutes at pH 6.8 and 1.2, respectively. Although no clear methodological root cause or analytical root cause could be established, it was found that these two tests showed the highest variability at 15 minutes throughout the study, with RSDs of 25.2 and 23.4%, respectively. The Student t-test showed a significant difference between the means obtained for Sequence 1 (i.e., Containers 1 - 6) and Sequence 2 (i.e., Containers 7 - 12) ( Figure 2 ).

[0095] Individual differences in shell rupture and hydration of the capsule contents leading to dissolution variability between Sequences 1 and 2 at early time points were considered the main contributing factors to the deviated results.

[0096] Since the dissolution results in the pivotal stability study were obtained at the same pH 1.2 (which showed an average of 84% of the label claim dissolved at 15 minutes), the results for the 93 mg dosage strength in this study could be compared with the data from the pivotal stability study. The average results in the stability study at 15 minutes were ≥ 90% at all 8 test points, indicating that the results obtained in this in vitro dissolution study did not represent the test product. For the comparison of the 62 mg dosage strength at pH 6.8, no corresponding stability data were available.

[0097] The metabolism of areilomol was studied in a human AME trial, which included metabolite profiling of plasma, urine, and feces (Study AALS - 002), and 3 of the most abundant metabolites (M2, M5, and M105) were quantified in plasma and urine as part of a clinical trial (Study OR - ARI - MET - 01). In addition, multiple in vitro studies were conducted to determine the structures of the metabolites and the enzymes involved in the metabolism of areilomol (see the non - clinical section for additional information).

[0098] In two clinical trials, areilomol was the major component in both plasma and urine. In AALS - 002, areilomol accounted for 43% of the total radioactivity circulating in plasma, and approximately 42% of the dose was excreted in urine as intact areilomol, which was consistent with the results from OR - ARI - MET - 01, where 43% of the dose was excreted in urine as areilomol.

[0099] In vitro and in vivo studies together showed that arelomol is metabolized by multiple pathways, and the major pathways are through glutathionylation, O-glucuronidation, and NO cleavage. The most abundant metabolites circulating in human plasma are the cysteine conjugate (M2), glucuronide (M5), and cleavage product M105, which are also the most abundant metabolites in urine.

[0100] All in vitro and in vivo metabolite studies conducted indicated that the metabolism of arelomol is similar between humans and non-clinical species. Results from metabolite profiling of plasma obtained from animals and humans documented that all human circulating metabolites are present in higher amounts in non-clinical species.

[0101] Pharmacokinetics of metabolites

[0102] The PK of arelomol and its metabolites were studied in six healthy young males aged ≥18 and ≤45 years in trial OR-ARI-MET-01. All subjects received 248 mg of arelomol (capsules) orally t.i.d. (744 mg / day) from Day 1 to Day 5 and a single morning dose on Day 6. Plasma and serum samples were collected up to 8 hours post-dose after the morning dose on Day 1, and plasma samples were collected before the morning doses on Days 2, 3, 4, 5, and 6 and up to 168 hours post-dose after the last dose on Day 6. Urine was collected quantitatively up to 24 hours post-morning dose on Days 1, 2, and 6. The plasma exposures of arelomol and its metabolites M2, M5, and M105 after single and multiple dosing are presented in Figure 3 and the pharmacokinetic parameters are summarized in Figure 4 .

[0103] In addition, the PK of arecolomol and its metabolites M2 and M105 were studied in a dedicated TQT trial (OR-ARI-TQT-01), which included a total of 34 healthy male subjects. Metabolite M5 was not studied in this trial because it is an O-glucuronide and does not present a toxicological concern (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 2012). The trial was completed in December 2020 and submitted to the EMA together with the response to D120. PK curves of arecolomol citrate, M2, and M105 were captured after single and multiple doses of arecolomol. The maximum plasma concentration observed for arecolomol citrate was 6900 ng / mL, for M2 was 2270 ng / mL, and for M105 was 833 ng / mL. On Day 1 and Day 3, after dosing, arecolomol was rapidly absorbed, and the median Tmax was 1 hour for both the therapeutic and supratherapeutic arecolomol doses. The mean arecolomol citrate exposure (AUC0-8) over an 8-hour dosing interval increased from 5610 h*ng / mL after the therapeutic 124 (200) mg dose to 18400 h*ng / mL after the supratherapeutic 372 (600) mg dose, both on Day 3. Thus, a three-fold increase in the dose level resulted in at least a three-fold higher mean exposure of arecolomol citrate.

[0104] Figure 5-8 It was shown that the mean terminal half-life (t1 / 2) of arecolomol citrate in plasma on Day 3 was similar for both the therapeutic and supratherapeutic doses of arecolomol (4.43 (11.6%) and 4.19 (9.7%) hours, respectively). Metabolite M2 showed a slightly longer t1 / 2 than arecolomol citrate (as observed on Day 3, 5.63 (10.4%) for the therapeutic dose and 5.40 (10.0%) for the supratherapeutic dose). As expected, the t1 / 2 of M105 could not be calculated because the terminal elimination phase of the M105 plasma curve was not reached on either Day 1 or Day 3 for the therapeutic and supratherapeutic arecolomol doses. Although the plasma curve on Day 1 showed an increasing M105 during the first 8-hour dosing interval, the M105 curve on Day 3 showed that the M105 metabolite reached steady state after dosing with both the therapeutic and supratherapeutic doses of arecolomol t.i.d.

[0105] Dose proportionality

[0106] Arecolomol was considered dose-proportional within the dose range of 62 to 372 mg t.i.d. (186 to 1116 mg / day). To study the dose proportionality of arecolomol after multiple doses, Cmax and AUC0-8 from all multiple-dose trials in healthy subjects were pooled, as Figure 9 shown.

[0107] Population modeling also confirmed that the pharmacokinetics of areilomol is linear within the dose range of 16 to 496 mg.

[0108] Time-dependence

[0109] The CL / F after single and multiple t.i.d. doses of areilomol was similar (34 to 61 L / h; Table 3-3). From population pharmacokinetic (popPK) analysis, no significant time-dependence or non-linearity was observed, as Figure 10 shown.

[0110] The pharmacokinetics of areilomol showed linearity with increasing dose rate and was stable over the course of treatment.

[0111] Areilomol showed dose-proportional pharmacokinetics with an oral bioavailability of at least 42%. The absolute bioavailability of areilomol in humans has not been studied. Relative to i.v. administration of areilomol, the absolute bioavailability of areilomol after oral administration was 84% in rats and 75% in dogs (based on AUC0-inf).

[0112] Peak plasma concentrations were reached within 0.25 to 3.0 hours (tmax). Food does not appear to have a relevant effect on pharmacokinetics. The effect of a high-fat meal on the pharmacokinetics of 62 mg areilomol was determined in Trials AALS-004 and AALS-011. In both studies, the 90% CIs for the AUC0-t and AUC0-inf and Cmax ratios were all within the range of 80% to 125%. The median tmax in the fed state was increased two-fold relative to the fasting state (3.0 versus 1.5 hours). However, since it is intended for long-term use, the difference in tmax was considered not clinically relevant.

[0113] After multiple doses of 62 to 372 mg t.i.d. (range 186 to 1116 mg / day), the accumulation index of areilomol (based on AUC0-8) was estimated to be 1.3 to 1.4. This is consistent with an average half-life of areilomol of 3.0 to 4.4 hours and t.i.d. administration. No time-dependence was observed for other pharmacokinetic parameters of areilomol.

[0114] PK in the target population

[0115] Figure 11 showed the exposure of areilomol (AUC 0-8h,ss 、C min,ss and C max,ssSummary statistics for

[0116] In addition, PK in the target population was characterized using a popPK model, in which an effect of age on the absorption rate was observed, i.e., the absorption rate appeared to increase with increasing age. In the D120 response, the applicant provided a more extensive discussion to justify the exclusion of age as a key covariate. The methods used for simulation were generally well-described and considered appropriate. It could be agreed that the simulation results demonstrated a minimal effect on Cmax and AUC between different age groups and that, therefore, the effect was considered negligible.

[0117] PK in special populations

[0118] Impaired renal function

[0119] The applicant has submitted the final clinical trial report of the renal impairment trial OR-ARI-REN-01 together with the D180 response. For the results, please refer to Section 3.3.9.11 of the Clinical Safety section, "Additional data provided in the D180 response".

[0120] Impaired liver function

[0121] Figure 12 The effect of liver impairment on the pharmacokinetics of arelosomol was investigated in an open-label, parallel-group, single-dose trial (OR-ARI-HEP-0) in 24 male and female subjects with mild and moderate liver impairment after a single dose of 248 mg arelosomol.

[0122] As Figure 13-14 shown, the potential effects of various intrinsic factors (including age, sex, race, and weight) have been examined using population PK analysis.

[0123] For subjects with a body weight above the median of 78.2 kg, arelosomol C maxss was 19% lower, and AUC (0-8)ss was 15% lower than in subjects with a body weight equal to or below 78.2 kg. The weight range in the clinical study was wide (11.7 - 114.2).

[0124] Without wishing to be bound by any particular theory, areilomol is considered an orally available small molecule that crosses the blood-brain barrier (BBB). It amplifies and sustains the cellular production of HSPs, particularly HSP70 (heat shock protein 70), by prolonging the activation of HSF1 and inducing the HSR. HSP70 and other HSPs are crucial for the correct folding and processing of the integral lysosomal membrane protein NPC1, including the specific I1061T misfolding mutation, which is the most common form of the mutated NPC1 in patients with NPC. The HSR is directly related to lysosomal integrity through HSP70-mediated stabilization of the lysosomal membrane and protection from cell death.

[0125] Thus, by amplifying the HSR, areilomol targets both protein misfolding and lysosomal dysfunction through a natural cellular defense mechanism. Therefore, areilomol has a novel mechanism of action that targets the root cause of the NPC etiology: NPC protein misfolding and lysosomal dysfunction.

[0126] The primary pharmacology proof of concept is based on non-clinical studies with human biomaterials. Briefly, studies have been conducted in NPC patient-derived fibroblasts and in - / - NPC mice, which are the most commonly used animal model for NPC. A dose-dependent (50, 100, 200, 400 μM) increase in the NCP1 protein was observed in all eight tested NPC patient fibroblast cell lines carrying different mutations, which were also present in the Phase 2 / 3 clinical trials, including I1061T, which is the most abundant missense mutation in NPC. In vivo studies in - / - NPC mice demonstrated that brain HSF1 and HSP70 were upregulated in response to areilomol treatment.

[0127] In clinical study CT-ORZY-NPC-002, PD markers were evaluated as exploratory endpoints, and the design of the study is described in the clinical efficacy section. The selected PD endpoints described in detail below were considered relevant as they are important markers of NPC.

[0128] Three key biomarkers were evaluated: HSP70, unesterified cholesterol, and cholestanetriol. Additional biomarkers evaluated were glycosphingolipid (GM3) and nLc4. A significant effect of areilomol exposure was determined for changes in GM3 levels in PBMCs (based on AUC 0-8,ss and C max,ss ), where higher exposure was associated with a decrease in GM3. No effect of areilomol exposure was determined for any of the other biomarkers analyzed.

[0129] As measured in PBMC, during the 12-month treatment period, the mean increase in HSP70 was higher in patients treated with arilomol compared to placebo; during 12 months, an average increase in the level of unesterified cholesterol in PBMC was observed in both placebo- and arilomol-treated patients. However, the average increase and thus the accumulation of unesterified cholesterol was much lower in the arilomol group compared to the placebo group. At 12 months, the level of cholestanetriol in serum decreased more in patients treated with arilomol compared to those treated with placebo.

[0130] Arilomol is metabolized via multiple pathways and the three main pathways are glutathionylation, O-glucuronidation and NO cleavage. The most abundant metabolites circulating in plasma are the cysteine conjugate of arilomol (M2) formed after hydrolysis of the glutathione conjugate, arilomol O-glucuronide (M5) and the cleavage product M105. Based on in vitro pharmacological studies (induction of HSP70 mRNA in HeLa cells after heat shock and induction of NPC1 protein in human fibroblasts) and its plasma exposure, none of the abundant metabolites M2, M5 or M105 are expected to contribute to the observed pharmacological effects of arilomol. The pharmacokinetic parameters of the most abundant metabolites M2, M5 and M105 have been studied in 6 healthy volunteers after quantification of metabolites in plasma and urine (OR-ARI-MET-01). In addition, the PK of arilomol and metabolites M2 and M105 were studied in 34 healthy male subjects in a TQT trial (OR-ARI-TQT-01). The trial was completed in December 2020 and was submitted to the EMA together with the response to D120LoQ. Metabolite M5 was not studied in this trial as it is an O-glucuronide and does not pose a toxicological concern (ICH 2012). According to the ICH E14 guideline, the results of the TQT trial constitute a negative TQT study. In addition, arilomol did not affect the heart rate or cardiac conduction of the subjects in the trial and was well tolerated by the subjects at both the therapeutic (372 mg / day) and supratherapeutic (1116 mg / day) doses. Both the therapeutic and supratherapeutic doses were higher compared to a liver trial (OR-ARI-HEP-01) in which subjects received a single dose of 248 mg arilomol and the subjects were exposed to multiple doses.

[0131] After single and multiple doses of arelomolol, PK profiles of arelomolol, M2 and M105 were recorded. The maximum plasma concentration observed for arelomolol citrate was 6900 ng / mL, for M2 was 2270 ng / mL and for M105 was 833 ng / mL. The mean arelomolol citrate exposure (AUC0-8) during an 8-hour dosing interval increased from 5610 h*ng / mL after a therapeutic 124 (200) mg dose to 18400 h*ng / mL after a supra-therapeutic 372 (600) mg dose, both on Day 3. Thus, a three-fold increase in dose level resulted in at least a three-fold higher mean exposure to arelomolol citrate. For both therapeutic and supra-therapeutic doses of arelomolol, the mean terminal half-life (t1 / 2) of arelomolol citrate in plasma on Day 3 was similar (4.43 (11.6%) and 4.·19 (9.7%) hours, respectively). Metabolite M2 showed a slightly longer t1 / 2 than arelomolol citrate (as observed on Day 3, 5.63 (10.4%) for the therapeutic dose and 5.40 (10.0%) for the supra-therapeutic dose). The t1 / 2 of M105 could not be calculated because the terminal elimination phase of the M105 plasma profile was not reached on either Day 1 or Day 3 for either the therapeutic or supra-therapeutic arelomolol doses. Although the Day 1 plasma profile showed rising M105 during the first 8-hour dosing interval, the Day 3 M105 profile showed that the M105 metabolite reached steady state after administration of both therapeutic and supra-therapeutic doses of arelomolol t.i.d.

[0132] In summary, the TQT trial, including a total of 34 healthy male subjects, showed no safety concerns after multiple doses of arelomolol up to 1116 mg / day and that exposure to both of the two metabolites (M2 and M105) reached steady state.

[0133] Therefore, based on the results from the TQT trial, no potential safety concerns related to the metabolites were found and thus dose reduction in patients with hepatic impairment may not be necessary.

[0134] Pharmacokinetic analysis showed that age had no significant effect on the pharmacokinetics of arelomolol in adults. However, the popPK model had estimated the Ka value to be approximately 0.338 h, CV = 48.5%, and suggested that age was an important factor for absorption. Simulations provided by the applicant demonstrated that Ka had a minimal effect on Cmax and AUC between different age groups and thus it was agreed that the expected effect was negligible.

[0135] Gender and body weight (BW) were found to be significant covariates affecting the exposure of arelolimus in adults. This effect may be related to the fixed dosing regimen in adults, where clearance increases with increasing body weight, and where women generally have lower body weights than men. In the pivotal Phase 2 / 3 CT-ORZY-NPC-002 trial, subjects with body weights of 8 to 55 kg were dosed by weight in predefined weight bands. Subjects above 55 kg received a fixed dose level of 124 mg t.i.d. arelolimus. The effects of gender (AUC0-8: 24%) and body weight (AUC0-8: 15%, body weight below and above 78 kg) observed in adults were small and considered not clinically relevant. Therefore, no dose adjustment of arelolimus is required based on gender or age. The same fixed dosing regimen can be administered to all patients with body weight > 55 kg.

[0136] Three dosage forms (capsules, capsules emptied and administered with food or beverage, capsules emptied and administered using a gastric tube) were used in the Phase 2 / 3 trial CT-ORZY-NPC-002 to support administration in populations including pediatric patients and patients with dysphagia. It was studied whether these different dosage forms would have an impact on the absorption rate (Ka). According to the applicant, the POP PK analysis showed that any effect of the dosage form was small and not clinically relevant.

[0137] During the clinical development of arelolimus for NPC, the drug product formulation has been changed with respect to the quantitative composition of the excipients. For the blinded phase of the clinical Phase 2 / 3 trial CT-ORZY-NPC-002, capsule formulations with an excess of excipient material for the lower capsule strengths were required to ensure blinding. Then, between the blinded phase and the open label (OL) phase of the CT-ORZY-NPC-002 trial, the capsule formulation was changed to optimize it for patients by reducing the capsule fill weight and the amount of excipient taken with each capsule. In addition, the gelatin capsule shell was replaced with a shell of hydroxypropyl methylcellulose (HPMC).

[0138] To further facilitate compliance and avoid taking multiple capsules three times a day, specific capsule strengths for each recommended dose were developed for products covering each of the 5 weight bands. Therefore, between the OL phase of the CT-ORZY-NPC-002 trial and the product to be marketed, the quantitative composition of the excipients was slightly changed for some strengths. To justify the use of the different pharmaceutical product formulations used during the clinical development of arelosomol for NPC and the formulation to be marketed, a biowaiver for bioequivalence studies based on the BCS (Biopharmaceutics Classification System) approach was requested. Generally, applications for BCS-based biowaivers are limited to pharmaceutical products in which the (multiple) drug substances exhibit high solubility and high permeability (BCS class I) or low permeability (BCS class III) and are known not to have a narrow therapeutic index. This concept applies to immediate-release solid pharmaceutical products intended for oral administration and having a systemic effect with the same drug form.

[0139] Under the conditions required in the corresponding guideline (BE guideline ICH9), the BCS prerequisite for high solubility has been demonstrated for arelosomol citrate. Regarding permeability, the applicant was required to provide additional data to clarify the BCS class (BCS class I or III) of arelosomol. In its response, the applicant provided data from a recently completed in vitro permeability study using a validated Caco-2 test system and a bioanalytical LC-MS method. Permeability was compared with the highly permeable and moderately permeable model drugs minoxidil and atenolol, respectively. In this study, the in vitro cell line permeability of arelosomol was similar to that of the highly permeable model drug minoxidil. In addition, the applicant was required to provide information on the possible excretion of arelosomol or its metabolites in feces via bile and whether the 12% of the recovered material in feces was the unchanged drug. The applicant responded that stability studies had shown arelosomol to be stable in gastric and intestinal fluids and that, therefore, the drug-related material collected in feces was expected to have its origin from previously absorbed arelosomol. In addition, in bile-duct-cannulated animals, the amount of drug-related material excreted in bile was similar to the amount excreted in feces in intact animals, which further indicated complete absorption of the oral dose of arelosomol. Based on the data provided, it was agreed that arelosomol met the requirements for high permeability, which supported its designation as a BCS class I drug.

[0140] To qualify for a BCS-based biowaiver for BCS class I drug substances, both the test product and the reference product should exhibit very rapid (average dissolution percentage ≥ 85% within ≤ 15 minutes) in vitro dissolution characteristics, or rapid (average dissolution percentage ≥ 85% within ≤ 30 minutes) and similar in vitro dissolution characteristics (i.e., based on f2 comparison).

[0141] For the reference product, both the 31 mg and 62 mg dosage strengths clearly showed very rapid dissolution characteristics.

[0142] For the test product, the 31 mg, 47 mg, and 124 mg capsule dosage strengths dissolved 85% or more of the labeled amount of drug within 15 minutes in all three dissolution media.

[0143] For the test product at the 62 mg dosage strength, 85% or more of the labeled amount of drug dissolved within 15 minutes at pH 1.2 and 4.5.

[0144] For the 93 mg dosage strength, 85% or more of the labeled amount of drug dissolved within 15 minutes at pH 4.5 and 6.8.

[0145] In the blinded phase, arelomol or placebo capsules were administered orally three times daily (t.i.d.) for 12 months.

[0146] If the administration of the IMP during the blinded phase occurred concomitantly with the administration of other concomitant medications, the IMP was administered first.

[0147] If desired, the IMP may be dissolved in 10 mL (i.e., 2 teaspoons) of liquid (water, apple juice, or milk) or in 1 tablespoon of soft food (yogurt or applesauce). In the dissolved or dispersed state, the IMP may also be administered via a gastric tube (if applicable).

[0148] A post hoc analysis was conducted excluding 4 patients with a more aggressive pattern of progression ( Figure 15 ).

[0149] Compared to a small subgroup of 11 patients without miglustat treatment at baseline, the baseline demographic characteristics and disease severity were more balanced between the arelomol and placebo groups for a larger subgroup of 39 patients using miglustat at baseline ( Figure 16 ).

[0150] Figure 17 An analysis of the change from baseline to month 12 in the 5 - domain and full - scale NPCCSS was shown for subgroups based on age at first neurological symptom.

[0151] Due to the small number of patients in this age span, 2 protocol - specified groups (<3 months and 3 months to <2 years) were collapsed into one group.

[0152] In one embodiment of the present technology, a method for diagnosing Niemann-Pick disease type C (NPC) in a human patient is provided, the method comprising: performing a first assay test on at least one biomarker of arimoclomol to quantify it as a first level; administering a pharmaceutical composition comprising arimoclomol or a pharmaceutically acceptable salt thereof; performing a second assay on at least one metabolite of arimoclomol; performing a third assay test on at least one biomarker of arimoclomol; and determining the difference between the first assay and the third assay. In another embodiment of the present technology, a method for treating a patient suspected of having NPC with a pharmaceutical composition or formulation of arimoclomol or a pharmaceutically acceptable salt thereof is provided, wherein the patient has at least one biomarker selected from the group consisting of HSP70, unesterified cholesterol, cholestanetriol, glycosphingolipid (GM3), and nLc4, the method comprising administering to the patient a pharmaceutical composition or formulation of arimoclomol or a pharmaceutically acceptable salt thereof, wherein administering arimoclomol or a pharmaceutically acceptable salt thereof to the patient results in one or more of the following: a) a decrease in GM3; b) an increase in HSP70; and / or c) a decrease in cholestanetriol. For example, administering arimoclomol to a patient with NPC reduces the accumulation of unesterified cholesterol in peripheral blood monocytes. In another example, administering arimoclomol to a patient with NPC reduces the accumulation of serum cholestanetriol levels.

[0153] In another embodiment of the present technology, a method for treating Niemann-Pick disease type C (NPC) in a human patient in need thereof is provided, wherein the patient has at least one biomarker selected from the group consisting of HSP70, unesterified cholesterol, cholestanetriol, glycosphingolipid (GM3), and nLc4, the method comprising administering to the patient a pharmaceutical composition or formulation of arimoclomol or a pharmaceutically acceptable salt thereof, wherein the amount of arimoclomol base in the composition or formulation is selected from the group consisting of 31 mg, 47 mg, 62 mg, 93 mg, or 124 mg of arimoclomol. The NPC is NPC-1 or NPC-2. Administering arimoclomol or a pharmaceutically acceptable salt thereof to the patient can result in one or more of the following: a) a decrease in GM3; b) an increase in HSP70; and / or c) a decrease in cholestanetriol. For example, administering arimoclomol to a patient with NPC reduces the accumulation of unesterified cholesterol in peripheral blood monocytes. In another example, administering arimoclomol to a patient with NPC reduces the accumulation of serum cholestanetriol levels.

[0154] In another embodiment of the present technology, a method for treating Niemann-Pick disease type C (NPC) in a human patient in need thereof is provided, wherein the patient has at least one biomarker selected from the group consisting of HSP70, unesterified cholesterol, cholestanetriol, glycosphingolipid (GM3), and nLc4. The method comprises: First, providing to the patient a pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition or formulation is provided in a capsule or other form or encapsulated therein, and wherein further, the amount of arilomol in the capsule (form) is selected from the group consisting of 31 mg, 47 mg, 62 mg, 93 mg, or 124 mg of arilomol (base); Second, opening the capsule and dispersing the pharmaceutical composition or formulation contents of the capsule into a liquid (e.g., a suspension in water) or a solid medium, wherein the liquid medium is selected from the group consisting of water or apple juice, and wherein the solid medium is selected from the group consisting of soft foods (e.g., applesauce, gelatin, baby food, etc., which are for neonates, pediatric, and other patients in need of such soft media); and Third, within 24 hours after dispersing the pharmaceutical composition or formulation of the capsule into the liquid or solid medium, administering to the patient the liquid or solid medium of step b) by a mode of administration selected from the group consisting of oral (i.e., swallowing or drinking), gastric insertion, or feeding tube.

[0155] In another embodiment of the present technology, a method for treating Niemann-Pick disease type C (NPC) in a human patient in need thereof is provided, the method comprising the steps of: First, providing to the patient a sufficient amount of a pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof, wherein the composition or formulation of arilomol is provided in a capsule or capsule form, and the sufficient amount is selected from the group consisting of 31 mg, 47 mg, 62 mg, 93 mg, and 124 mg of arilomol (in base form); Second, opening the capsule or capsule form and dispersing the pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof in at least one liquid or at least one solid medium to form at least one dispersion; and Finally Third, within a twenty-four-hour time period after the pharmaceutical composition or formulation or a pharmaceutically acceptable salt thereof is dispersed in at least one liquid or solid medium, administering the dispersion to the patient; that is to say, the dispersion is administered to the patient within 24 hours of the dispersion being formed. In these embodiments, the liquid medium can be a member or a combination of one or at least one selected from the group consisting of water and apple juice. Additionally, the solid medium in these embodiments can be selected from the group consisting of at least one soft food (e.g., applesauce, gelatin, baby food, etc., which are for neonates, pediatric, and other patients in need of such soft media).

[0156] In another embodiment of the present technology, the administration of a pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof, or a dispersion of a pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof in a liquid or solid medium, can be carried out orally, such as but not limited to inserting into the mouth and swallowing, through a nasogastric tube, through a gastrostomy tube, or through a non-gastrostomy tube. In some embodiments of the present technology, the patient is over two years of age. In an alternative embodiment of the present technology, the patient is two years of age or younger (such as an infant).

[0157] In some embodiments of the present technology, the pharmaceutically acceptable salt of arilomol is arilomol citrate. In other embodiments of the present technology, Niemann-Pick disease type C (NPC) is subtype NPC1 (NPC1 or NPC-1) or subtype NPC2 (NPC2 or NPC-2).

[0158] In another embodiment of the present technology, there is provided a monotherapy method for treating a patient with NPC using a pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof. For example, in some of these monotherapy methods, the patient is not suitable for treatment with another drug, such as for example miglustat.

[0159] In an alternative embodiment of the present technology, there is provided a dual or combination therapy method for treating a patient with NPC using a pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof in addition to a pharmaceutical composition or formulation of a sufficient amount of miglustat. The sufficient amount of miglustat or its pharmaceutical composition or formulation can be a therapeutically effective amount.

[0160] In another embodiment of the present technology, the administration of a pharmaceutical composition or formulation of arilomol or a pharmaceutically acceptable salt thereof to a patient in need can result in the formation of at least one or more metabolites. The metabolite(s) can be present in the composition or formulation before administration, or can be formed and present in the dispersion during the dispersion step discussed herein, or can be formed after administration to the patient. The at least one or more metabolites are selected from the group consisting of: M1, M2, M3, M4, M5, M7, M39, M104, M105, and M107. In one example of the present technology, the at least one metabolite is one or more of the following: M2, M5, or M105.

[0161] In another embodiment of the present technology, the dispersion step of the pharmaceutical composition or formulation of arilomol or its pharmaceutically acceptable salt results in at least 80% of the pharmaceutical composition or formulation of arilomol or its pharmaceutically acceptable salt being suspended or dissolved in at least one liquid medium. For example, within 15 minutes after the dispersion / dispersing step, at least 80% of the pharmaceutical composition or formulation of arilomol or its pharmaceutically acceptable salt is dissolved in the liquid medium. In one embodiment of the present technology, within 15 minutes of the dispersion step (i.e., dispersing arilomol citrate into the liquid medium), at least 80% of the pharmaceutical composition or formulation of arilomol citrate is dissolved in the liquid medium. The at least one liquid medium has a pH range of from about 1.2 to about 6.8. In one embodiment, the liquid medium has a pH range of from about 1.2 to about 4.5.

Claims

1. A method for treating Niemann-Pick disease type C (NPC) in a human patient in need thereof, the method comprising the steps of: Providing to the patient a pharmaceutical composition or formulation of an amount sufficient of arilomel or a pharmaceutically acceptable salt thereof; Wherein the composition or formulation of arilomel is provided in a capsule dosage form; And Wherein the pharmaceutical composition or formulation of an amount sufficient of arilomel or a pharmaceutically acceptable salt thereof is selected from the group consisting of 31 mg, 47 mg, 62 mg, 93 mg, and 124 mg of arilomel (base form); Opening the capsule dosage form and dispersing the pharmaceutical composition or formulation of arilomel or a pharmaceutically acceptable salt thereof in at least one liquid or at least one solid medium to form at least one dispersion; Wherein the liquid medium is at least one member selected from the group consisting of water and apple juice; Wherein the solid medium is at least one soft food; And Administering the dispersion to the patient within a twenty-four-hour time period after the pharmaceutical composition or formulation or a pharmaceutically acceptable salt thereof is dispersed or suspended in the at least one liquid or solid medium.

2. The method of claim 1, wherein the administering step is carried out orally via a nasogastric tube, via a gastrostomy tube, or via a non-gastrostomy tube.

3. The method of claim 1, wherein the pharmaceutically acceptable salt of arilomel is arilomel citrate.

4. The method according to any one of claims 1-3, wherein the patient is under two years of age.

5. The method of claim 1, wherein the soft food is applesauce.

6. The method of claim 1, wherein the liquid medium is apple juice.

7. The method according to claim 1 or 2, wherein the liquid medium is water; and Wherein the dispersion is administered to the patient via at least one gastrostomy tube or non-gastrostomy tube.

8. The method according to any one of claims 1-7, wherein the Niemann-Pick disease type C is subtype NPC1 or subtype NPC2.

9. The method according to any one of claims 1-8, further comprising the step of administering to the patient an amount sufficient of miglustat.

10. The method according to any one of claims 1-8, wherein the treatment method is monotherapy with arilomel or a pharmaceutically acceptable salt thereof.

11. The treatment method according to any one of claims 1-10, wherein the pharmaceutical composition or formulation of arilomel or a pharmaceutically acceptable salt thereof is metabolized by the patient into at least one metabolite of arilomel.

12. The treatment method of claim 11, wherein the at least one metabolite is a member selected from the group consisting of: M1, M2, M3, M4, M5, M7, M39, M104, M105, and M107.

13. The method of claim 12, wherein the metabolite is M2, M5, or M105.

14. The method of claim 1, wherein at least 80% of the pharmaceutical composition or formulation of arilomel or a pharmaceutically acceptable salt thereof dissolves in the liquid medium within 15 minutes after the dispersing step.

15. The method according to claim 3, wherein at least 80% of the arilomol citrate is dissolved in the liquid medium within 15 minutes after the dispersion step.

16. The method according to claim 14 or 15, wherein the liquid medium has a pH range of from about 1.2 to about 6.

8.

17. The method according to claim 16, wherein the liquid medium has a pH range of from about 1.2 to about 4.5.

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