Eliglustat for the treatment of gaucher disease

Abstract

Disclosed are methods of treating Gaucher disease in a pediatric patient. The method comprises (i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and (ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient. The dosage is specified depending on whether the pediatric patient is assessed as being a poor, an intermediate, or an extensive metabolizer, as well as the age and the weight of the pediatric patient. Also disclosed are suspensions of a formulation of eliglustat, or a pharmaceutically acceptable salt thereof.

Description

ELIGLUSTAT FOR THE TREATMENT OF GAUCHER DISEASECROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 663,290, filed June 24, 2024, the entire disclosure of which is incorporated by reference herein.TECHNICAL FIELD

[0002] Disclosed herein are methods for treating Gaucher disease in pediatric patients.BACKGROUND

[0003] Glycosphingolipids (GSLs) are a class of naturally-occurring compounds which have a multitude of biological functions, including the ability to promote cell growth, cell differentiation, adhesion between cells or between cells and matrix proteins, binding of microorganisms and viruses to cells, and metastasis of tumor cells. GSLs are derived from glucosylceramide (GlcCer), which is produced from ceramide and UDP-glucose by the enzyme UDP-glucose: / V-acylsphingosine glucosyltransferase (GlcCer synthase). The structure of ceramide is shown below:Ceramide

[0004] The accumulation of GSL has been linked to a number of diseases, including Tay- Sachs, Gaucher, and Fabry diseases (see, for example, U.S. Patent No. 6,051,598). Compounds which inhibit glucosylceramide (GlcCer) synthase lower GSL concentrations and have been reported to be useful for treating a patient with one of the aforementioned diseases.

[0005] Eliglustat is a glucosylceramide synthase inhibitor currently approved in the United States as a first-line oral therapy for adults with Gaucher disease type 1 (GDI) who are CYP2D6 extensive metabolizers, intermediate metabolizers, or poor metabolizers.

[0006] Eliglustat (chemical name: N-((17?,2J?)-l-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-l- hydroxy-3-(pyrrolidin-l-yl)propan-2-yl)octanamide) has the structure of Formula (I):

[0007] U.S. Patent No. 7,196,205, for example, describes the preparation and physical and biological properties of the compound of Formula (I).

[0008] Eliglustat is sold in the United States under the brand name Cerdelga® as a hemitartrate(la)- which is also referred to herein as eliglustat tartrate.

[0009] The preparation of eliglustat tartrate is described in, for example, WO2011 / 066352.

[0010] The use of eliglustat or a pharmaceutically acceptable salt thereof for treating patients who are CYP2D6 extensive metabolizers, intermediate metabolizers, or poor metabolizers is described in WO2011 / 066352.

[0011] It is well known that the therapeutic needs of and drug exposure in children are sufficiently different than those of adults such that specific studies of medications in children are required. Moreover, children may be unable to swallow an oral dosage form such as a capsule of eliglustat or a pharmaceutically acceptable salt thereof produced for adult patients. Children may also find the adult solid dosage forms to have an unpleasant taste. There have been no clinical trials thus far to study the safety and effectiveness of eliglustat for treating Gaucher disease in pediatric patients or to determine the dosage that is therapeutically effective in such patients. Effective and acceptable forms of medication for treating Gaucher disease in pediatric patients are needed.

[0012] All documents, including scientific articles, patent publications and applications, and the like, referenced in the present disclosure are hereby incorporated by reference in their entirety.BRIEF SUMMARY

[0013] The present disclosure describes methods of treating Gaucher disease in pediatric patients.

[0014] One aspect of the present disclosure is a method of treating Gaucher disease in a pediatric patient, the method comprising: (i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and (ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer.

[0015] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is: from 42 mg twice per day to 84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.

[0016] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is: 42 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg; or 84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs 25 kg or above.

[0017] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.

[0018] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.

[0019] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

[0020] In some embodiments, the CYP2D6 genotyping has been performed by PCR or by microarray based testing.

[0021] In some embodiments, the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

[0022] In some embodiments, the Gaucher disease is type 1 Gaucher disease.

[0023] In some embodiments, the method further comprises co-administering a therapeutically effective amount of an enzyme replacement therapy (ERT) in addition to administering the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the patient was previously treated with enzyme replacement therapy (ERT).

[0025] In some embodiments, the patient is stable on enzyme replacement therapy (ERT).

[0026] In some embodiments, the enzyme replacement therapy comprises administering a therapeutically effective amount of imiglucerase.

[0027] In some embodiments, the enzyme replacement therapy comprises administering 30 U / kg to 130 U / kg every two weeks.

[0028] In some embodiments, the eliglustat, or a pharmaceutically acceptable salt thereof is administered as a suspension.

[0029] In some embodiments, the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.

[0030] In some embodiments, the suspension is stable for 90 days at 25 °C / 60% RH.

[0031] In some embodiments, the suspension is stable for 30 days at 40 °C / 75% RH.

[0032] In some embodiments, wherein the suspension is stable for 90 days at 2 °C to 8 °C.

[0033] In some embodiments, the suspension is an oral suspension.

[0034] Another aspect of the present disclosure is a method of treating Gaucher disease in a pediatric patient, the method comprising: (i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and (ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being a poor metabolizer.

[0035] In some embodiments, the therapeutically effective amount of eliglustat is from 21 mg once per day to 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof,measured in base form wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.

[0036] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is: 21 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg; 42 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg; or 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

[0037] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 21 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.

[0038] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.

[0039] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

[0040] In some embodiments, the CYP2D6 genotyping has been performed by PCR or by microarray based testing.

[0041] In some embodiments, the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

[0042] In some embodiments, the Gaucher disease is type 1 Gaucher disease.

[0043] In some embodiments, the method further comprises co-administering a therapeutically effective amount of imiglucerase in addition to administering the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the patient was previously treated with enzyme replacement therapy (ERT).

[0045] In some embodiments, the patient is stable on enzyme replacement therapy (ERT).

[0046] In some embodiments, the enzyme replacement therapy comprises administering a therapeutically effective amount of imiglucerase.

[0047] In some embodiments, the enzyme replacement therapy comprises administering 30 U / kg to 130 U / kg every two weeks.

[0048] In some embodiments, the eliglustat, or a pharmaceutically acceptable salt thereof is administered as a suspension.

[0049] In some embodiments, the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.

[0050] In some embodiments, the suspension is stable for 90 days at 25 °C / 60% RH.

[0051] In some embodiments, the suspension is stable for 30 days at 40 °C / 75% RH.

[0052] In some embodiments, the suspension is stable for 90 days at 2 °C to 8 °C.

[0053] In some embodiments, the suspension is an oral suspension.

[0054] Yet another aspect of the present disclosure is eliglustat or a pharmaceutically acceptable salt thereof for use in a method of treating Gaucher disease in a pediatric patient, the method comprising: (i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and (ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer.

[0055] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is from 42 mg twice per day to 84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form of eliglustat, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.

[0056] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is: from 42 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg; or 84 mg twice perday of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs 25 kg or above.

[0057] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.

[0058] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.

[0059] In some embodiments, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

[0060] In some embodiments, the CYP2D6 genotyping has been performed by PCR or by microarray based testing.

[0061] In some embodiments, the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

[0062] In some embodiments, the Gaucher disease is type 1 Gaucher disease.

[0063] In some embodiments, a therapeutically effective amount of an enzyme replacement therapy (ERT) is co-administered in addition to administering the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof.

[0064] In some embodiments, the patient was previously treated with enzyme replacement therapy (ERT).

[0065] In some embodiments, the patient is stable on enzyme replacement therapy (ERT).

[0066] In some embodiments, the enzyme replacement therapy comprises administering a therapeutically effective amount of imiglucerase.

[0067] In some embodiments, the enzyme replacement therapy comprises administering 30 U / kg to 130 U / kg every two weeks.

[0068] In some embodiments, the eliglustat, or a pharmaceutically acceptable salt thereof is administered as a suspension.

[0069] In some embodiments, the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.

[0070] In some embodiments, the suspension is stable for 90 days at 25 °C / 60% RH.

[0071] In some embodiments, the suspension is stable for 30 days at 40 °C / 75% RH.

[0072] In some embodiments, the suspension is stable for 90 days at 2 °C to 8 °C.

[0073] In some embodiments, the suspension is an oral suspension.

[0074] Yet another aspect of the present disclosure is a suspension comprising eliglustat, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and a suspending vehicle.

[0075] In some embodiments, the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.

[0076] In some embodiments, the suspension is stable for 90 days at 25 °C / 60% RH.

[0077] In some embodiments, the suspension is stable for 30 days at 40 °C / 75% RH.

[0078] In some embodiments, the suspension is stable for 90 days at 2 °C to 8 °C.

[0079] In some embodiments, the suspension is an oral suspension.

[0080] Yet another aspect of the present disclosure is an article of manufacture comprising: a packaging material; eliglustat, or a pharmaceutically acceptable salt thereof; and a label or package insert contained within the packaging material indicating a method to prepare and administer a suspension of eliglustat, or a pharmaceutically acceptable salt thereof in a pediatric patient.

[0081] Yet another aspect of the present disclosure is a package comprising eliglustat, or a pharmaceutically acceptable salt thereof, and a label, the label comprising a printed statement which informs a prospective user i) that eliglustat, or pharmaceutically acceptable salt thereof, is indicated for treatment of Gaucher disease type 1 in a pediatric patient and ii) a method to prepare and administer a suspension of eliglustat, or a pharmaceutically acceptable salt thereof in the pediatric patient.BRIEF DESCRIPTION OF DRAWINGS

[0082] FIG. 1 shows the geometric mean eliglustat CmaXand AUCo-r at Week 52 for CYP2D6 EM pediatric participants with the revised dosing regimens during the PAP according to the study performed in Example 1.

[0083] FIG. 2 shows the mean absolute change from baseline in hemoglobin (g / dL) for Cohort 1 over 52 weeks.

[0084] FIG. 3 shows the mean percent change from baseline in platelet count (xlO9 / L) over 52 weeks.

[0085] FIG. 4 shows the mean percent change from baseline of liver volumes (MN) over time in Cohort 1 - FAS (Full Analysis Set).

[0086] FIG. 5 shows the mean percent change from baseline of spleen volumes (MN) over time for participants that received eliglustat monotherapy.DETAILED DESCRIPTION

[0087] It is to be understood that the disclosed embodiments are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. While illustrated embodiments are provided, it will be understood that they are not intended to limit the present disclosure to those embodiments. On the contrary, the present disclosure is intended to cover all alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art, and which may be included within the present disclosure as defined by the appended claims.

[0088] The section headings used herein are for organizational purposes only and are not to be construed as limiting the desired subject matter in any way. In the event that any literature incorporated by reference contradicts any term defined in this specification, this specification controls.

[0089] It should be noted that, as used in this specification and the appended claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “a conjugate” includes a plurality of conjugates and reference to “a cell” includes a plurality of cells and the like.”

[0090] Numeric ranges are inclusive of the numbers defining the range. Measured and measurable values are understood to be approximate, taking into account significant digits and the error associated with the measurement. Also, the use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” are not intended to be limiting. It is to be understood that both the foregoing general description and detailed description are exemplary and explanatory only and are not restrictive of the teachings.

[0091] As used above, and throughout the description of the invention, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0092] As used herein, the term “coadministered,” “coadministering,” “in combination,” or “concurrently taking” refers to being administered or administering at the same time, in the same day or within a period of 24 hours, particularly within a period of 12 hours.

[0093] As used herein, the term “treating” or “treatment” of a disease includes: preventing the disease, e.g., causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease inhibiting the disease, e.g., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, e.g., causing regression of the disease or its clinical symptoms.

[0094] As used herein, the term “therapeutically effective amount” refers to an amount of eliglustat that would be recommended for a patient to take or that a doctor would prescribe the patient to take according to the present disclosure that is effective in producing the desired therapeutic effect. The dose of eliglustat is calculated based on its free base form. It should be understood that eliglustat can be administered as a pharmaceutically acceptable salt, particularly as a hemitartrate, and the amount of salt administered should be adjusted accordingly.

[0095] As used herein, the term “patient” refers to a human who is in need of or is receiving a medical treatment.

[0096] As used herein, the term “pediatric” refers to a human who is less than 18 years of age. In some embodiments, the term “pediatric” refers to a human who is less than 15 years of age.

[0097] As used herein, the term “pharmaceutically acceptable salt” refers to the salts of the compound of the present disclosure that can be used in medicinal preparations.

[0098] As used herein, the term “pharmaceutically acceptable excipient” refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present disclosure to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. The said excipients are selected, in accordance with the pharmaceutical form and method of administration desired, from the customary excipients, which are known to a person skilled in the art.

[0099] As used herein, the term “a compound for use . .. ,” for example, shall be understood as being equivalent to the term “use of a compound for . .. ” or “use of a compound for the preparation of a medicament for use in . . .”.

[0100] Eliglustat is metabolized by the liver, primarily by cytochrome P450 enzymes. Cytochrome P450s (“CYPs”) are the principal hepatic xenobiotic metabolizing enzymes. There are eleven xenobiotic-metabolizing cytochrome P450s expressed in a typical human liver (i.e., CYP1A2, CYP2A6, CYP2B6, CYP2C8 / 9 / 18 / 19, CYP2D6, CYP2E1 and CYP3A4 / 5). MainlyCYP2D6 and to a lesser extent CYP3A4 are the primary cytochrome P450 isoforms that are responsible for metabolizing eliglustat and its pharmaceutically active salts, such as eliglustat tartrate. The level of activity of some P450 enzymes such as CYP2D6 differs according to the individual CYP2D6 phenotype. For example, individuals can be classified as poor, intermediate, extensive, and ultra rapid CYP2D6 metabolizers.

[0101] A patient is typically assessed as being a poor, intermediate, extensive, or ultra rapid CYP2D6 metabolizer through genotyping, although rarely the genotype cannot be determined (indeterminate metabolizer).

[0102] For example, a patient can be a poor P450 metabolizer as a result of low expression of a P450 enzyme. In such instances, the low expression can be assessed by determining P450 enzyme expression in the patient, i.e., genotyping the patient for the P450 enzyme. For example, expression of CYP2D6 is commonly assessed by PCR (McElroy et.al. “CYP2D6 Genotyping as an Alternative to Phenotyping for Determination of Metabolic Status in a Clinical Trial Setting”, AAPS Pharmsi (2000) 2(4) article 33) or by microarray based pharmacogenomic testing. As such, the patient can be conveniently genotyped for P450 expression (e.g., CYP2D6) prior to the initiation of treatment and administered an adjusted effective amount, if necessary.

[0103] For the CYP2D6 gene, there are four predicted phenotypes:As used herein, a “poor CYP2D6 metabolizer,” “poor metabolizer,” or “PM” carries two mutant alleles, which result in complete loss of enzyme activity.As used herein, an “intermediate CYP2D6 metabolizer,” “intermediate metabolizer,” or “IM” possesses one reduced activity allele and one null allele.As used herein, an “extensive CYP2D6 metabolizer,” “extensive metabolizer,” or “EM” possesses at least one and no more than two normal functional alleles.As used herein, an “ultra rapid CYP2D6 metabolizer” or “ultra rapid metabolizer” carries multiple copies (3-13) of functional alleles and produce excess enzymatic activity.

[0104] Because eliglustat is metabolized mainly by CYP2D6 and to a lesser extent by CYP3 A, eliglustat concentration may be increased in patients when co-administered with certain drugs that are CYP2D6 enzyme inhibitors. Examples of weak CYP2D6 inhibitors include, but are not limited to, escitalopram, abiraterone, diphenhydramine, amiodarone, deramciclane, desvenlafaxine, fosdevirine, daclatasvir / asunaprevir / beclabuvir, oral contraceptives, osilodrostat, propafenone, ritonavir, cimetidine, clobazam, cobicistat, lorcaserin, celecoxib, felodipine, fluvoxamine,gefitinib, hydroxychloroquine, sertraline, vemurafenib, echinacea, escitalopram, hydralazine, panobinostat, ranitidine, verapamil, alogliptin, diltiazem, dulaglutide, lopinavir / ritonavir, sarpogrelate, artesunate / pyronaridine, imatinib, and febuxostat. Examples of moderate CYP2D6 inhibitors include, but are not limited to, duloxetine, terbinafine, moclobemide, mirabegron, cinacalcet, dronedarone, rolapitant, cimetidine, and tipranavir / ritonavir. Examples of strong CYP2D6 inhibitors include, but are not limited to, paroxetine, fluoxetine, quinidine, bupropion, and dacomitinib.

[0105] Patients who are poor CYP2D6 metabolizers have little or no CYP2D6 function, so eliglustat metabolism would primarily be via the CYP3A pathway in these patients. Eliglustat metabolism in these patients may be further impaired as a result of being treated with certain drugs that are CYP3A enzyme inhibitors. For example, examples of weak CYP3A inhibitors include, but are not limited to, amlodipine, cilostazol, fluvoxamine, goldenseal, isoniazid, ranitidine, and ranolazine. Examples of moderate CYP3 A inhibitors include, but are not limited to, erythromycin, ciprofloxacin, fluconazole, diltiazem, verapamil, aprepitant, atazanavir, darunavir, fosamprenavir, imatinib, cimetidine, amprenavir, casopitant, crizotinib, faldaprevir, ledipasvir, netupitant, nilotinib, tofisopam, dronedarone, cimetidine, and cyclosporine. Examples of strong CYP3A inhibitors include, but are not limited to, ketoconazole, clarithromycin, itraconazole, cobicistat, indinavir, lopinavir, ritonavir, saquinavir, telaprevir, tipranavir, posaconazole, voriconazole, telithromycin, conivaptan, boceprevir, idelalisib, mibefradil, nefazodone, nelfmavir, elvitegravir / ritonavir, danopravir / ritonavir, and troleandomycin.

[0106] Eliglustat (Cerdelga®, CD) is indicated for adults with Gaucher disease type 1 and was approved in the U.S. in 2014 and in the EU in 2015 under Orphan designation. In the U.S., Food and Drug Administration approved for an adult patient 84 mg twice daily of eliglustat to patients who are CYP2D6 extensive metabolizers or intermediate metabolizers, and 84 mg once daily of eliglustat to patients who are poor metabolizers. Prior to the studies described herein, there have been no clinical trials to study the safety and effectiveness of eliglustat for treating Gaucher disease (GD) in pediatric patients or to determine the dosage that is therapeutically effective in such patients.

[0107] One aspect of the present disclosure provides a method of treating Gaucher disease in a pediatric patient, the method comprising: (i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, oran extensive CYP2D6 P450 metabolizer; and (ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer.

[0108] In some embodiments, for the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is: from 42 mg twice per day to 84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at leastl5 kg.

[0109] In some embodiments, for the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.

[0110] In some embodiments, for the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs equal to or greater than 25 kg[0U1] In some embodiments, for the pediatric patient assessed as being an extensive metabolizer, and wherein the patient is concurrently taking a weak CYP2D6 inhibitor or a strong, moderate, or weak CYP3A inhibitor, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg once per day if the pediatric patient is aged from 6 years to less than 18 years.

[0112] In some embodiments, for the pediatric patient assessed as being an extensive metabolizer, and wherein the patient has mild hepatic impairment (Child-Pugh Class A), the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years.

[0113] In some embodiments, for the pediatric patient assessed as being an extensive metabolizer, and wherein the patient has mild, moderate, or severe renal impairment, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years.

[0114] In some embodiments, the Gaucher disease is type 1 Gaucher disease. In some embodiments, the Gaucher disease is type 3 Gaucher disease.

[0115] Another aspect of the present disclosure provides a method of treating Gaucher disease in a pediatric patient, the method comprising: (i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and (ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being a poor metabolizer.

[0116] In some embodiments, for the pediatric patient assessed as being a poor metabolizer, the therapeutically effective amount of eliglustat is from 21 mg once per day to 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form.

[0117] In some embodiments, for the pediatric patient assessed as being a poor metabolizer, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is: 21 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg; or 42 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg, or 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

[0118] In some embodiments, for the pediatric patient assessed as being a poor metabolizer, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 21 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years and weighs from 15 kg to less than 25 kg.

[0119] In some embodiments, for the pediatric patient assessed as being a poor metabolizer, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.

[0120] In some embodiments, for the pediatric patient assessed as being a poor metabolizer, the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof, is 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

[0121] In some embodiments, the Gaucher disease is type 1 Gaucher disease (GDI). In some embodiments, the Gaucher disease is type 3 Gaucher disease (GD3).

[0122] In some embodiments of the present disclosure, the patient has previously received enzyme replacement therapy (ERT). In other aspects, the patient was stable on ERT prior to initiation of treatment with eliglustat, or pharmaceutically acceptable salt thereof.

[0123] Yet another aspect of the present disclosure provides the method of treating Gaucher disease in a pediatric patient as described above and the method further comprising coadministering a therapeutically effective amount of an ERT in addition to administering the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof. A non-limiting example of an ERT is imiglucerase.

[0124] For their therapeutic use, eliglustat and pharmaceutically acceptable salts thereof are generally introduced into pharmaceutical compositions. These pharmaceutical compositions comprise eliglustat or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0125] The one or more pharmaceutically acceptable excipients are chosen according to the pharmaceutical form and the method of administration desired, from the usual excipients which are known to those skilled in the art. By way of example, a dose of eliglustat or a pharmaceutically acceptable salt thereof, in capsule form, may correspond to the following example: A capsule for oral use comprising 21 mg of eliglustat, measured as a free base (equivalent to 25 mg of the hemitartrate salt), microcrystalline cellulose, lactose monohydrate, hypromellose and glyceryl behenate. By way of another example, a dose of eliglustat or a pharmaceutically acceptable salt thereof, in capsule form, may correspond to the following example: A capsule for oral use comprising 42 mg of eliglustat, measured as a free base (equivalent to 50 mg of the hemitartrate salt), microcrystalline cellulose, lactose monohydrate, hypromellose and glyceryl behenate.

[0126] In some embodiments, the eliglustat, or a pharmaceutically acceptable salt thereof is administered orally to the pediatric patient. Non-limiting examples of an oral dosage form include, for example, a tablet, a pill, or a capsule.

[0127] Yet another aspect of the present disclosure provides the method of treating Gaucher disease in a pediatric patient as described above and the eliglustat, or a pharmaceutically acceptable salt thereof is administered orally to the pediatric patient in the form of a suspension. Thesuspension comprises a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof and a suspending vehicle.

[0128] In some embodiments, the eliglustat, or a pharmaceutically acceptable salt thereof is administered twice per day as a suspension comprising 21 mg of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, and a suspending vehicle.

[0129] In some embodiments, the eliglustat, or a pharmaceutically acceptable salt thereof is administered twice per day as a suspension comprising 42 mg of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, and a suspending vehicle.

[0130] In some embodiments, the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.

[0131] In some embodiments, the suspension is stable for 90 days at 25 °C / 60% RH.

[0132] In some embodiments, the suspension is stable for 30 days at 40 °C / 75% RH.

[0133] In some embodiments, the suspension is stable for 90 days at 2 °C to 8 °C.

[0134] In some embodiments, the suspension is an oral suspension.EXAMPLES

[0135] The present disclosure may be better understood by reference to the following nonlimiting examples, which are exemplary of the disclosure. They should in no way be construed, however, as limiting the breath of the scope of the disclosure.

[0136] EXAMPLE 1

[0137] As part of the European Pediatric Investigational Plan (PIP) requirement, eliglustat was subject of a Phase 3 study in pediatric participants with type 1 Gaucher disease (GDI) and type 3 Gaucher disease (GD3). An open label, two-cohort (with and without imiglucerase (Cerezyme®)), multicenter study was carried out to evaluate safety, pharmacokinetics (PK), and efficacy of eliglustat in pediatric participants with GDI and GD3.

[0138] Cohort 1 (eliglustat monotherapy):

[0139] Criteria for inclusion: Participants with GDI or GD3 who met pre-specified therapeutic goals [(a) hemoglobin level for ages 2 to <12 years: >11.0 g / dL; for ages 12 to <18 years: >11.0 g / dL for females, and >12.0 g / dL for males, and (b) platelet count >100,000 / mm3, and (c) spleen volume <10.0 multiples of normal (MN), and (d) liver volume <1.5 MN, and (e) absence of Gaucher disease related pulmonary disease and symptomatic bone disease as defined for Cohort2)] and have been on enzyme replacement therapy (ERT) treatment for >2 years prior to study enrollment and at the time of study enrollment.

[0140] The main efficacy endpoint was change from baseline to Week 52 in the hematologic and organ volume parameters and quality of life.

[0141] Cohort 2 (eliglustat plus imiglucerase combination therapy):

[0142] Criteria for inclusion: Participants with GDI or GD3, who had severe clinical manifestation(s) of Gaucher disease (related pulmonary disease, or symptomatic bone disease, or persistent thrombocytopenia) despite ERT for >3 years prior to study enrollment and at the time of study enrollment.

[0143] The main efficacy endpoint was the percentage of participants after Week 52 with improvement in the severe manifestation that made the participant eligible for inclusion in the study.

[0144] Study design:

[0145] The study included three phases: A primary analysis treatment period (PAP; Day 1 to Week 52), a long-term treatment period (LTP; Week 53 to Week 104), and an extension period (EP; Week 105 to the end of study).

[0146] Cohort 1 participants received eliglustat monotherapy as primary study treatment for at least 52 weeks. Rescue treatment of imiglucerase monotherapy was provided to participants who met any of the rescue criteria defined as a significant clinical decline while on eliglustat monotherapy. The rescue treatment comprised of administering imiglucerase at a dose of 60 U / kg every 2 weeks.

[0147] Cohort 2 participants received eliglustat plus imiglucerase combination therapy as primary study treatment. Imiglucerase was given to the participants every 2 weeks for a minimum of 52 weeks. The dose administered was equivalent to the dose of ERT patients were receiving before enrollment for Cohort 2. After Week 52, participants switched to eliglustat monotherapy if they had achieved the desired clinical response defined as improvement of the Gaucher disease severe manifestation(s) that led to inclusion in Cohort 2, or otherwise remained on combination therapy through Week 104.

[0148] Participants in both cohorts continued into the EP if clinical benefit was demonstrated on eliglustat monotherapy prior to Week 104.

[0149] An interim analysis of safety (all phases), pharmacokinetics (PK; PAP) and efficacy (PAP) endpoints was performed when the participants had completed the PAP.

[0150] Study participants: The study enrolled participants in two age groups, 12 to <18 years and 2 to <12 years, respectively, in a sequential manner. A total of 57 participants with Gaucher disease (GD) were enrolled as shown in Table 1. Across the 2 cohorts, there were 55 CYP2D6 EMs, 1 IM, and 1 PM. No participants were in the 10 to <15 kg weight category and 3 participants were aged 2 and <6 years.

[0151] Table 1Number of Participants in Cohorts 1 and 2Cohort Age group GD Type 1 GD Type 3 TotalCohort 1 12 to <18 years 30 3 332 to <12 years 16 2 18Cohort 2 12 to <18 years 1 2 32 to <12 years 2 1 3Total 49 8 57

[0152] There was only one participant (GD3) who discontinued during the PAP for reasons related to the COVID-19 pandemic.

[0153] Dosing regimen: Participants were dosed according to their CYP2D6 predicted phenotype and weight category as shown in Table 2. The proposed initial doses for age groups by CYP2D6 genotype and by body weight were modeled using a pediatric physiologically-based pharmacokinetic (PBPK) modeling. The proposed dose was aligned with the adult dosing approach approved for IMs and EMs. For PMs, a lower dose (42 mg QD) was proposed (compared to 84 mg QD recommended in adult) to be more conservative and to have a lower exposure in the pediatric population. However, doses were adjusted, as needed, during the trial for the following reasons:

[0154] 1) As the initial dose regimen was proposed for pediatrics based on a physiologically- based pharmacokinetic (PBPK) modeling to target exposures comparable to adults, a planned interim PK analysis of the first 10 EM participants in each age group was performed at Week 2 (steady-state) to assess the exposure of eliglustat and to allow dose adjustment to achieve the targetexposure. Based on this analysis, an updated dose regimen was applied for EM and IM participants in the 15 kg to <25 kg and 25 kg to <50 kg weight categories, as shown in Table 2.

[0155] 2) In addition, if individual observed exposure, both Cinax and AUCO-T, at Week 2 was confirmed to be below the 5thpercentile of the target adult exposure range, the dose would have been adjusted.

[0156] 3) Finally, as participants grew, eliglustat doses were adjusted when the participants met the weight criteria for the next weight category.

[0157] During the PAP, 27 participants had one dose adjustment and 1 participant had two dose adjustments.Table 2Initial and revised dose regimens based on interim PK analyses (either sub-group or individual analysis)BID=twice daily; QD=once daily; EM=extensive metabolizer; IM=intermediate metabolizer; PM=poor metabolizer. a. The adjustment of doses in relative age and body-weight groups after the subgroup PK analysis is presented in the outlined box in bold font. b. The new dose regimens used for participants who required dose adjustment based on the results of PK analyses (either sub-group or individual analysis) c. Four participants received 126 mg BID as their PK exposure at Week 2 after repeated doses of 84 mg BID were confirmed to be below the 5thpercentile of the PBPK -predicted adult range. d. No patients were enrolled in those dosing groups.

[0158] Results

[0159] Primary Endpoint: Safety

[0160] Study treatment in both cohorts (eliglustat monotherapy and eliglustat plus imiglucerase combination therapy, respectively) was generally well tolerated in both age groups (2 to <12 years and 12 to <18 years) and in both Gaucher disease types (GDI and GD3). Most treatment-emergent adverse events (TEAE) were mild or moderate and not related to study treatment.

[0161] Over the course of the study, across the two cohorts, 53 participants (93.0%) experienced at least one TEAE, with a total number of 360 TEAEs reported regardless of the study treatment received. In Cohort 1, 94.1% of participants experienced at least one TEAE on primary study treatment. Two (33.3%) out of 6 participants who received rescue therapy experienced at least one TEAE while on rescue treatment (imiglucerase monotherapy). In Cohort 2, 83.3% of participants experienced at least one TEAE on primary study treatment. One (50.0%) out of 2 participants who switched to eliglustat monotherapy experienced at least one TEAE.

[0162] Serious TEAEs (SAEs) were only reported in Cohort 1. Six (6) participants (11.8%) experienced a total of 9 SAEs; 5 participants experienced 8 SAEs on primary study treatment (pneumonia, splenomegaly, hepatomegaly, arthralgia [2 events], facial bones fracture, lower limb fracture [due to fall]), and 1 participant experienced an SAE while in Rescue Step 1 (60 U / kg imiglucerase monotherapy every other week) (COVID-19). Seven (7) participants (4 GDI and 3 GD3) in Cohort 1 discontinued primary study treatment due to AEs. Treatment-emergent adverse events of special interest (AESIs) were only reported in Cohort 1 on primary study treatment. Three (3) participants (5.9%) experienced a total of 5 AESIs ([vasovagal] syncope, sinus tachycardia, accidental overdose [3x]).

[0163] In Cohort 1, the most frequently reported TEAEs were in the system order classes (SOC) infections and infestations (64.7%), gastrointestinal disorders (43.1%), and musculoskeletal and connective tissue disorders (29.4%). The most frequent preferred terms (PT) (in >10% of participants) were nasopharyngitis (23.5%), COVID-19 (21.6%), headache (13.7%), arthralgia (13.7%), dyspepsia (13.7%), pharyngitis (11.8%) and vomiting (11.8%).

[0164] In Cohort 2, the most frequent PTs were: nasopharyngitis, COVID-19, otitis externa, vomiting, diarrhea, and pain in extremity (all reported in 2 of the 6 participants; 33.3%).

[0165] Overall, the safety profile of eliglustat in the pediatric Gaucher disease patient populations studied was acceptable.

[0166] Primary Endpoint: Pharmacokinetics (PK)

[0167] PK data from both cohorts were pooled and analyzed using noncompartmental method. A summary on the eliglustat PK results at Week 52 with the revised dosing regimen during the PAP (i.e., >25 kg and 84 mg BID, >15 - <25 kg and 42 mg BID) are provided in Table 3.Table 3Mean ± SD (geometric mean) [90% CI of geometric mean] plasma pharmacokinetic parameters of eliglustat in CYP2D6 EM pediatric participants by body weight groups\lote: 90% Confidence Interval (CI) of the parameters was only calculated if N of the group is equal or greater than 5 (N > 5) a. PK data from participants in both age groups are pooled for descriptive statistical summary b. Median (Min : Max) c. PK data from participants in the body weight groups of >25 - < 50 kg and >= 50 kg were combined for the descriptive statistics

[0168] FIG. 1 shows the geometric mean eliglustat Cmaxand AUCO-T at Week 52 for CYP2D6 EM pediatric participants with the revised dosing regimens during the PAP. Solid circles represent geometric mean of Cmax and AUCO-T and error bars represent 90% CI. PK data from participants in the two age groups with the body weight of >25 to <50 kg (N = 17), >50 kg (N = 22), or >25 kg (N = 39) were pooled for the calculation of geometric mean and 90% CI. Due to the small sample size (N=3) of participants with the body weight group of >15 - <25 kg dosed at 42 mg BID, onlytheir individual PK parameters are presented (open circles). The dotted line represents the target adult exposure (5thand 95thpercentile predicted by PBPK modeling) and the adult predicted mean Cmax and AUCo-zare 27.2 ng / mL and 190 h*ng / mL, respectively.

[0169] Following multiple doses of eliglustat BID in CYP2D6 EM participants, median time to reach maximum plasma concentrations (tmax) occurred at about 1 to 2 hours post-dose. As seen in FIG. 1, the 90% confidence interval (CI) of the geometric mean of PK parameters was generally within the target exposure (5th-95thpercentile of PBPK-predicted eliglustat exposure in adults) in CYP2D6 EM participants. Eliglustat exposures in CYP2D6 PM and IM participants (N = 1 for each) were generally within the target exposure range in the corresponding adult subjects.

[0170] Secondary Endpoint: Efficacy

[0171] Cohort 1 (eliglustat monotherapy)

[0172] The main efficacy endpoints evaluated were similar to those previously evaluated in adults with GDI, i.e., change from baseline to Week 52 in the hematologic (hemoglobin level and platelet count) and organ volume (both liver and spleen) parameters. In Cohort 1, 46 participants were classified as GDI and 5 were classified as GD3.

[0173] Overall, 96% of participants in Cohort 1 maintained hemoglobin, platelets, and liver and spleen volume within therapeutic goals. Of the 5 participants with GD3, one left due to COVID-19, 2 qualified for rescue therapy during the PAP, and there was a trend toward decline in the remaining two participants. As the sample size of participants with GD3 is very limited, no meaningful conclusions can be drawn.Hemoglobin: At baseline, the mean hemoglobin level for participants who received eliglustat monotherapy were within normal limits (age >2 years to <12 years: >10.5 g / dL; males aged >12 years: >12 g / dL; females aged >12 years: >11 g / dL). The mean level was 13.65 g / dL (1.06). At Week 52, the mean (SD) hemoglobin level for participants in Cohort 1 was 13.24 g / dL (1.21). The mean (SD) absolute change from baseline to Week 52 was -0.41 g / dL (1.02). Over the 52- week period, the mean absolute change from baseline in hemoglobin (g / dL) is shown graphically in FIG. 2.Platelets: At baseline, the mean platelet counts were within normal limits (>150 x 109 / L); however, 4 participants entered into the study with levels consistent with mild thrombocytopenia (120 to <150 x 109 / L). The mean (SD) platelet count for participants in the cohort was 215.33 x 109 / L. (51.6). At Week 52, the mean (SD) platelet count was 196.25 x 109 / L (64.12). The mean(SD) percentage change from baseline was -7.87% (22.71). Over the 52-week period, the mean percent change from baseline in platelet count is shown graphically in FIG. 3.Liver Volume: At baseline, the mean (SD) liver volume in MN for the participants who received eliglustat monotherapy was 0.98 MN (0.19). Forty-seven participants had values within the no / mild hepatomegaly range (<1.25 MN) at baseline, while 4 participants had moderate hepatomegaly (>1.25 to <2.5 MN). At Week 52, the mean (SD) liver volume in MN of the participants was 0.98 (0.21). The mean (SD) percentage change from baseline in liver volume was 0.95% (13.45) as shown in FIG. 4. All participants on eliglustat monotherapy (Cohort 1) sustained values at or below the therapeutic goal for liver volume (<1.5 MN) at Week 52.Spleen Volume: The mean (SD) baseline spleen volume for the cohort was 3.36 MN (1.54). Most participants had no / mild splenomegaly at baseline (<5.0 MN), 8 participants had moderate splenomegaly (>5.0 MN to <15.0 MN). Over the 52-week period, mean (SD) spleen volumes of the participants changed by 3.67% (25.47) for a mean volume of 3.40 (1.60) (displayed in FIG. 5). FIG. 5 shows that all participants on eliglustat monotherapy (Cohort 1) sustained values at or below the therapeutic goal for spleen volume (<10.0 MN) at Week 52.

[0174] Five participants (10%) in Cohort 1 qualified for rescue therapy in the PAP. Three (1 GDI, 2 GD3) qualified due to an increase in spleen volume from baseline >35%. Two participants (GDI) qualified for rescue therapy based on the Investigator’s opinion that they warranted treatment with ERT.

[0175] Cohort 2 (eliglustat plus imiglucerase)

[0176] The main efficacy endpoint is the percentage of participants with improvement in the severe manifestation that made the participant eligible for inclusion in Cohort 2. A total of 6 participants were enrolled in Cohort 2. While two of the three participants enrolled due to symptomatic bone disease met the desired clinical response by Week 52 and were switched to eliglustat monotherapy, the three participants who enrolled based on the presence of Gaucher disease related pulmonary disease did not reach the desired clinical response by Week 52. In the 4 participants who did not reach the desired clinical response, a trend was observed toward improvement in the manifestation that led to their enrollment in this cohort as indicated by the respective Investigator.

[0177] Conclusion

[0178] Safety: Study treatment in both monotherapy and combination therapy cohorts was generally well tolerated. Most TEAEs were mild or moderate and not related to study treatment. Seven (7) participants receiving eliglustat monotherapy discontinued study treatment due to AEs and qualified for rescue therapy during the study. Overall, the safety profile of eliglustat in the pediatric Gaucher disease patient populations studied was acceptable and consistent with the established safety profile of eliglustat in adults with GDI and as expected in a comparable pediatric population.

[0179] PK: For pediatric participant administered with updated dosing regimen (Table 2), the 90% Cis of the geometric mean of the PK parameters (Cmaxand AUCO-T) were generally within the target exposure (5lh- 95thpercentile of PBPK -predicted eliglustat exposure in adults) in CYP2D6 EM participants (Table 3). Eliglustat exposures in CYP2D6 PM and IM participant (N = 1 for each) were generally within the predicted target exposure in the corresponding adult subjects.

[0180] Efficacy: For the 51 participants receiving eliglustat monotherapy, 96% maintained hemoglobin, platelets, and liver and spleen volume within therapeutic goals. As the sample size of participants with GD3 is very limited, no meaningful conclusions can be drawn. For the 6 participants receiving eliglustat plus imiglucerase, combination therapy provided no clear evidence of clinically meaningful changes in the severe manifestations during the 52-week primary analysis period as expected.

[0181] EXAMPLE 2

[0182] Two allometric scaled PopPK models were developed based on the CYP2D6 phenotype, as a single PopPK model could not adequately describe the eliglustat PK due to the large impact of the CYP2D6 phenotype on eliglustat PK.

[0183] The first model, for the CYP2D6 extensive metabolizer and intermediate metabolizer population, used a dataset composed of 606 subjects (193 healthy volunteers, 357 adult patients and 56 pediatric patients) enrolled into phase 1 to phase 3 clinical studies. The second model, for the CYP2D6 poor metabolizer population, had a dataset composed of 35 subjects (20 healthy volunteers, 14 adult patients and 1 pediatric patient). These models were then used to compute individual exposure parameters of pediatric patients from the clinical study described in Example 1, which were then summarized by dose and body weight. These allometric scaled models were also used to simulate the eliglustat PK in specific subgroups in order to evaluate the adequacy of the dose recommendations of eliglustat in pediatric population. Simulations performed with thefinal models allowed estimates of exposures to support the following dose recommendation depending on the CYP2D6 phenotype and the body weight group of the pediatric patient. Exposures computed in extensive metabolizer, intermediate metabolizer, and poor metabolizer patients, with different body weight (BW) groups, were then compared to the adult dosing regimens of 42 and 84 mg. In almost all of cases, the simulated dosing regimens provided exposure estimates which were in the range of adult simulated values (90% confidence intervals of the geometric mean of pediatric values were included in the 5th-95thpercentiles intervals of adult values). In virtual pediatric C YP2D6 extensive metabolizer and intermediate metabolizer patients, simulated PK exposures at 42 mg BID dose with BW 15 to <25 kg and at 84 mg BID dose with BW >25 kg generally matched the adult PK exposure at 84 mg BID (approved doses). In virtual pediatric CYP2D6 PM patients, simulated PK exposures at 84 mg QD with BW >50 kg matched the adult PK exposure at 84 mg QD (approved dose). The simulated median PK parameters (i.e. Cmax and AUCo-Q at 42 mg QD with BW 25 to <50 kg and at 21 mg QD with BW 15 to <25 kg were below the adult PK exposure at 84 mg by about 16 to 18% and 33 to 35%, respectively. Accordingly, the dosing regimens described herein could not be reasonably predicted prior to the studies described in Examples 1 and 2.

[0184] EXAMPLE 3

[0185] Suspensions of eliglustat were prepared in various suspension vehicles and they were evaluated.

[0186] Suspensions of eliglustat were prepared in the following suspension / dispersion vehicles: methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet Cerdelga® capsules were emptied and mixed with the selected vehicles and screened for suitability for pediatric oral dosage use.

[0187] The details of the dispersing vehicles screened is provided in Table 4.Table 4

[0188] The different vehicles were characterized for their physical properties like appearance, taste, color, odor, density, pH, and viscosity.

[0189] The dispersions of eliglustat in the various dispersion vehicles were subjected to organoleptic evaluation like grittiness, color, mouth feel, odor, flavor, taste, after taste, and overall acceptability. The dispersions were also tested for dispersibility by storing them undisturbed for 24 hours and observing for sedimentation. Based on the organoleptic and dispersibility evaluation, the following observations were made: 1) Dispersions made with 1% Methyl Cellulose Gel and SyrSpend® showed a uniform initial dispersion and were also re-dispersible after 24 hours upon shaking, while dispersions made with Simple Syrup, Ora Plus® and Ora Sweet® were not redispersible and showed sedimentation or lump formation; 2) Dispersion made with SyrSpend® had better organoleptic values to any of the other dispersions; 3) The constituents of Ora Plus® and Ora Sweet® had high molecular weight polymers like carboxymethylcellulose sodium, xanthan gum, carrageenan and multiple excipients like microcrystalline cellulose, buffers, flavors, and sweeteners, which may result in lump formation during compounding.

[0190] In-Use Stability Evaluation

[0191] An in-use stability study was designed to mimic the conditions at the time of use by a patient, where the dispersion would be compounded using a dispersion vehicle, filled in glassbottles, and simulated for daily dispensing at minimum of 1 mL using a measuring cup and an oral syringe.

[0192] In-use stability study using SyrSpend® SF PH4: 100 mL of vehicle with Syr Spend® SF PH4 cherry flavor was mixed with 10 eliglustat 84 mg capsules in a glass bottle to form a dispersion. The glass bottle was stored for a duration of 90 days at two ICH recommended stability conditions: 25°C / 60% RH and at 2°C to 8°C. Chemical and microbiological analyses were performed.

[0193] In-Use stability study using an Ora Plus® and Ora Sweet® Blend Vehicle in 3 :7 Ratio: A dispersion of eliglustat was prepared by combining 10 eliglustat 84 mg capsules with 60 mL Ora Plus® in a glass bottle, to which 140 mL of Ora Sweet® was added. The glass bottle was stored for a duration of 90 days at two ICH recommended stability conditions of: 25°C / 60% RH and at 2 °C to 8°C. Chemical and microbiological analyses were performed.

[0194] The chemical and microbiological analyses of the above two dispersions were performed at in-use stability time points of: Initial, day 15, day 30, day 45, day 60, day 75, and day 90. The analyses included measuring assay values, related substances, pH, density, redispersibility, organoleptic properties, and microbial contamination. Based on these evaluations, it was determined that SyrSpend® as well as a blend of Ora Plus®: Ora Sweet® (3:7) are suitable as suspending vehicles to disperse eliglustat capsule and are suitable for use for 90 days.

[0195] Stability Evaluation

[0196] The SyrSpend® as well as the blend of Ora Plus®: Ora Sweet® (3:7) dispersions were prepared as described above for in-use stability study. Stability evaluations of the dispersions were performed to estimate the impact of storage of the prepared dispersion from the date of issuance from a pharmacy until the patient opens the bottle for use. The study was performed per ICH recommended stability conditions of 40°C / 75% RH (accelerated), 25°C / 60%RH (room temperature), and 2°C to 8°C (refrigerated conditions). The chemical and microbiological analyses of the above two dispersions were performed at time points of: Initial, 1 month, 2 months, and 3 months.

[0197] The acceptance criteria for the dispersion were adopted from the existing product specification of the capsule formulation. The stability studies showed that the suspension made with SyrSpend® as well as with a blend of Ora Plus®: Ora Sweet® (3:7) meet these acceptance criteria at room temperature (25°C / 60%RH) and refrigerated (2°C to 8°C) conditions. In addition,the dispersion made with a blend of Ora Plus®: Ora Sweet® (3:7) meets these acceptance criteria at accelerated conditions (40°C / 75%RH). However, at accelerated conditions (40°C / 75%RH), the impurity profde of the dispersion made with SyrSpend® exceeded the limits of acceptance criteria at the end of 90 days, citing that the formulation cannot be stored more than 30 days in extreme environments of temperature and humidity.

[0198] EXAMPLE 4

[0199] A method of compounding eliglustat, such as for the administration of a suspension to a pediatric patient, is provided below.

[0200] Instructions to pharmacist, for example, for compounding using SyrSpend® or a blend of Ora Plus®: Ora Sweet® (3:7):

[0201] 1) Open and empty the contents of 40 capsules of 21 mg or 10 capsules of 84 mgCerdelga® capsules as per physician instructions into a suitable container or mortar. Note: The weight of contents should be 2.7 g; discard any excess.

[0202] 2) (a) For the dispersion made with SyrSpend®, take 200 mL of SyrSpend® SF PH 4 in a suitable measuring device. Pour half the quantity, approximately 100 mL of suspending vehicle, in a suitable bottle or mortar.

[0203] 2) (b) For the dispersion made with a blend of Ora Plus®: Ora Sweet® (3:7), take 60 mL of Ora Plus® in a suitable measuring device. Pour half the quantity, approximately 30 mL of Ora Plus®, in a suitable bottle or mortar.

[0204] 3) (a) For the dispersion made with SyrSpend®, transfer the Cerdelga® capsule blend of Step 1) into the bottle or the mortar.

[0205] 3) (b) For the dispersion made with a blend of Ora Plus®: Ora Sweet® (3:7), transfer the Cerdelga® capsule blend of Step 1) into the mortar and triturate with pestle until the powder is mixed with the Ora Plus®. The triturated mixture from the mortar should be accurately transferred (using a funnel if feasible) to a 250 mL amber glass bottle. Rinse the mortar and pestle with remaining quantity of Ora Plus® and transfer to glass bottle. Using an appropriate graduated cylinder, measure 140 mL Ora Sweet®. Using a suitable funnel, transfer Ora Sweet® into the glass bottle.

[0206] 4) Close the child resistant (CR) cap of the bottle and shake vigorously or triturate the solution in the mortar and pestle until the powder is mixed with the suspending vehicle forapproximately 3 minutes. The solution from the mortar should be accurately transferred (using a funnel) to a suitable bottle.

[0207] 5) Transfer the remaining suspending vehicle to the bottle and shake well for 3 minutes or add the remaining suspending vehicle to the mortar, rinse well and transfer the liquid to the bottle and shake well for 3 minutes. Note: The final volume of dispersion is 200 mL, and the label claim is 4.2 mg / mL of eliglustat.

[0208] 6) Write the “use before” date of the constituted oral suspension on the bottle label and store the bottle in a cool place. Note: The use before date should not exceed 90 days from the date of dispersion preparation.

[0209] 7) Dispense the bottle along with a suitable measuring cup and 10 mL oral syringe.

[0210] Example of Instructions to Patients:

[0211] 1) Avoid contact with the contents of the oral formulation with your skin or eyes. If you come in contact with the contents of the oral formulation, wash your skin well with soap and water or rinse your eyes well with plain water. Do not use oral formulation after the “use before” date on the bottle. Always use the oral syringe provided to you by the pharmacist.

[0212] 2) To take a dose of Cerdelga® liquid oral suspension, you will need the bottle of medicine, an oral syringe, and an oral measuring cup provided along with the liquid oral suspension medicine.

[0213] 3) With the child-resistant cap on the bottle, shake the bottle well for 25 seconds before each use.

[0214] 4) Open the bottle by pressing downward firmly on the child resistant cap and turning it in the direction of the arrow.

[0215] 5) Pour the required approximate quantity of the liquid suspension into the measuring cup.

[0216] 6) Check the dose in milliliters (mL) as prescribed by your doctor. Find this number on the oral syringe. Push the plunger down toward the tip of the oral syringe. Pull the plunger to withdraw the prescribed dose from the measuring cup. If you see air bubbles in the oral dispenser, fully push in the plunger so that the oral solution flows back into the measuring cup. Then withdraw your prescribed dose.

[0217] 7) Place the tip of the oral syringe in the patient’s mouth. Slowly push down the oral syringe plunger until the oral syringe is empty.

[0218] 8) Pour the remaining amount from the measuring cup back into the bottle. Put the child resistant cap back on the bottle. Return the bottle back to a cool place.

[0219] 9) Hand-wash the oral syringe and the measuring cup with water after each use. Do not throw away the oral syringe and the measuring cup.

[0220] EXEMPLARY IMPLEMENTATIONS

[0221] The following examples are given as specific illustrations of the present disclosure. It should be understood, however, that the present disclosure is not limited to the specific details set forth in the following categories of exemplary implementations.

[0222] Category A:Al . A method of treating Gaucher disease in a pediatric patient, the method comprising:(i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and(ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer.A2. The method of Al, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is from 42 mg twice per day to 84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form of eliglustat, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.A3. The method of Al or A2, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is:42 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg; or84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs 25 kg or above.A4. The method of any one of A1-A3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.A5. The method of any one of A1-A3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.A6. The method of any one of A1-A3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.A7. The method of any one of A1-A6, wherein the CYP2D6 genotyping has been performed by PCR or by microarray based testing.A8. The method of any one of A1-A7, wherein the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.A9. The method of any one of A1-A8, wherein the Gaucher disease is type 1 Gaucher disease.A10. The method of any one of A1-A9, further comprising co-administering a therapeutically effective amount of an enzyme replacement therapy (ERT) in addition to administering the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof.Al 1. The method of any one of A1-A10, wherein the patient was previously treated with enzyme replacement therapy (ERT).A12. The method of any one of Al-Al l, wherein the patient is stable on enzyme replacement therapy (ERT).A13. The method of any one of A10-A12, wherein the enzyme replacement therapy comprises administering a therapeutically effective amount of imiglucerase.A14. The method of any one of A10-A13, wherein the enzyme replacement therapy comprises administering 30 U / kg to 130 U / kg every two weeks.A15. The method of any one of A1-A14, wherein the eliglustat, or a pharmaceutically acceptable salt thereof is administered as a suspension.Al 6. The method of Al 5, wherein the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.A17. The method of A15 or A16, wherein the suspension is stable for 90 days at 25 °C / 60% RH.A18. The method of any one of A15-A17, wherein the suspension is stable for 30 days at 40 °C / 75% RH.Al 9. The method of any one of Al 5-Al 8, wherein the suspension is stable for 90 days at 2 °C to 8 °C.A20. The method of any one of A15-A19, wherein the suspension is an oral suspension.

[0223] Category B:Bl. A method of treating Gaucher disease in a pediatric patient, the method comprising:(i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and(ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being a poor metabolizer.B2. The method of Bl, wherein the therapeutically effective amount of eliglustat is from 21 mg once per day to 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.B3. The method of B 1 or B2, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is:21 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg;42 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg; or84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.B4. The method of any one of B1-B3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 21 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.B5. The method of any one of B1-B3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.B6. The method of any one of B1-B3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.B7. The method of any one of B1-B6, wherein the CYP2D6 genotyping has been performed by PCR or by microarray based testing.B8. The method of any one of B1-B7, wherein the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.B9. The method of any one of B1-B8, wherein the Gaucher disease is type 1 Gaucher disease.BIO. The method of any one of B1-B9, further comprising co-administering a therapeutically effective amount of imiglucerase in addition to administering the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof.B 11. The method of any one of B 1-B 10, wherein the patient was previously treated with enzyme replacement therapy (ERT).B12. The method of any one of Bl-11, wherein the patient is stable on enzyme replacement therapy (ERT).B13. The method of any one of B10-B12, wherein the enzyme replacement therapy comprises administering a therapeutically effective amount of imiglucerase.B14. The method of any one of B10-B13, wherein the enzyme replacement therapy comprises administering 30 U / kg to 130 U / kg every two weeks.Bl 5. The method of any one of Bl -Bl 4, wherein the eliglustat, or a pharmaceutically acceptable salt thereof is administered as a suspension.B16. The method of Bl 5, wherein the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.B17. The method of B15 or Bl 6, wherein the suspension is stable for 90 days at 25°C / 60% RH.B18. The method of any one of B15-B17, wherein the suspension is stable for 30 days at 40 °C / 75% RH.B19. The method of any one of B15-B18, wherein the suspension is stable for 90 days at 2 °C to 8 °C.B20. The method of any one of B15-B19, wherein the suspension is an oral suspension.

[0224] Category C:Cl. Eliglustat or a pharmaceutically acceptable salt thereof for use in a method of treating Gaucher disease in a pediatric patient, the method comprising:(i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and(ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer.C2. The eliglustat or a pharmaceutically acceptable salt thereof of Cl, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is from 42 mg twice per day to 84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form of eliglustat, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.C3. The eliglustat or a pharmaceutically acceptable salt thereof of Cl or C2, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is:from 42 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg; or84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs 25 kg or above.C4. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C1-C3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.C5. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C1-C3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.C6. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C1-C3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.C7. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C1-C6, wherein the CYP2D6 genotyping has been performed by PCR or by microarray based testing.C8. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C1-C7, wherein the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.C9. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C1-C8, wherein the Gaucher disease is type 1 Gaucher disease.C10. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C1-C9, further comprising co-admini st ering a therapeutically effective amount of an enzyme replacement therapy (ERT) in addition to administering the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof.Cl 1. The eliglustat or a pharmaceutically acceptable salt thereof of any one of Cl -CIO, wherein the patient was previously treated with enzyme replacement therapy (ERT).C12. The eliglustat or a pharmaceutically acceptable salt thereof of any one of Cl-Cl 1, wherein the patient is stable on enzyme replacement therapy (ERT).C13. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C10-C12, wherein the enzyme replacement therapy comprises administering a therapeutically effective amount of imiglucerase.C14. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C10-C13, wherein the enzyme replacement therapy comprises administering 30 U / kg to 130 U / kg every two weeks.Cl 5. The eliglustat or a pharmaceutically acceptable salt thereof of any one of Cl 1-C14, wherein the eliglustat, or a pharmaceutically acceptable salt thereof is administered as a suspension.C16. The eliglustat or a pharmaceutically acceptable salt thereof of Cl 5, wherein the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.C 17. The eliglustat or a pharmaceutically acceptable salt thereof of C 15 or C 16, wherein the suspension is stable for 90 days at 25 °C / 60% RH.C18. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C15-C17, wherein the suspension is stable for 30 days at 40 °C / 75% RH.C 19. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C 15-C 18, wherein the suspension is stable for 90 days at 2 °C to 8 °C.C20. The eliglustat or a pharmaceutically acceptable salt thereof of any one of C 15-C 19, wherein the suspension is an oral suspension.

[0225] Category D:DI. A suspension comprising eliglustat, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and a suspending vehicle.D2. The suspension of DI, wherein the suspending vehicle is one or more selected from methyl cellulose gel, sucrose in water, SyrSpend SF PH4, Ora Plus, and Ora Sweet.D3. The suspension of DI or D2, wherein the suspension is stable for 90 days at 25 °C / 60% RH.D4. The suspension of any one of D1-D3, wherein the suspension is stable for 30 days at 40 °C / 75% RH.D5. The suspension of any one of D1-D4, wherein the suspension is stable for 90 days at 2 °C to 8 °C.D6. The suspension of any one of D1-D5, wherein the suspension is an oral suspension.

[0226] Category E:El . An article of manufacture comprising: a packaging material; eliglustat, or a pharmaceutically acceptable salt thereof; anda label or package insert contained within the packaging material indicating a method to prepare and administer a suspension of eliglustat, or a pharmaceutically acceptable salt thereof in a pediatric patient.

[0227] Category F:Fl. A package comprising eliglustat, or a pharmaceutically acceptable salt thereof, and a label, the label comprising a printed statement which informs a prospective user i) that eliglustat, or pharmaceutically acceptable salt thereof, is indicated for treatment of Gaucher disease type 1 in a pediatric patient and ii) a method to prepare and administer a suspension of eliglustat, or a pharmaceutically acceptable salt thereof in the pediatric patient.

[0228] From the foregoing, those skilled in the art will appreciate that certain modifications can also be made to the present disclosure without departing from the scope of the same. The above description should not be construed as limiting, but merely as exemplifications of particular embodiments. Those skilled in the art will envision other modifications within the scope and spirit of the claims appended hereto.

Claims

CLAIMS1. A method of treating Gaucher disease in a pediatric patient, the method comprising:(i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and(ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer.

2. The method of claim 1, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is from 42 mg twice per day to 84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form of eliglustat, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.

3. The method of claim 1 or 2, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is:42 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg; or84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs 25 kg or above.

4. The method of any one of claims 1-3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.

5. The method of any one of claims 1-3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.

6. The method of any one of claims 1-3, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

7. The method of any one of claims 1-6, wherein the CYP2D6 genotyping has been performed by PCR or by microarray based testing.

8. The method of any one of claims 1-7, wherein the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

9. The method of any one of claims 1-8, wherein the Gaucher disease is type 1 Gaucher disease.

10. The method of any one of claims 1-9, wherein the patient was previously treated with enzyme replacement therapy (ERT).

11. The method of any one of claims 1-10, wherein the patient is stable on enzyme replacement therapy (ERT).

12. A method of treating Gaucher disease in a pediatric patient, the method comprising:(i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and(ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being a poor metabolizer.

13. The method of claim 12, wherein the therapeutically effective amount of eliglustat is from 21 mg once per day to 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.

14. The method of claim 12 or 13, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is:21 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg;42 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg; or84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

15. The method of any one of claims 12-14, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 21 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.

16. The method of any one of claims 12-14, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.

17. The method of any one of claims 12-14, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg once per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

18. The method of any one of claims 12-17, wherein the CYP2D6 genotyping has been performed by PCR or by microarray based testing.

19. The method of any one of claims 12-18, wherein the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

20. The method of any one of claims 12-19, wherein the Gaucher disease is type 1 Gaucher disease.

21. The method of any one of claims 12-20, wherein the patient was previously treated with enzyme replacement therapy (ERT).

22. The method of any one of claims 12-19, wherein the patient is stable on enzyme replacement therapy (ERT).

23. Eliglustat or a pharmaceutically acceptable salt thereof for use in a method of treating Gaucher disease in a pediatric patient, the method comprising:(i) assessing the pediatric patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, an intermediate, or an extensive CYP2D6 P450 metabolizer; and(ii) administering a therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof to the pediatric patient assessed as being an extensive metabolizer or an intermediate metabolizer.

24. The eliglustat or a pharmaceutically acceptable salt thereof of claim 23, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is from 42 mg twice per day to 84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form of eliglustat, wherein the pediatric patient is aged from 6 years to less than 18 years and weighs at least 15 kg.

25. The eliglustat or a pharmaceutically acceptable salt thereof of claim 23 or 24, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is:from 42 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg; or84 mg twice per day of eliglustat, or a pharmaceutically acceptable salt thereof, measured in base form, if the pediatric patient is aged from 6 years to less than 18 years and weighs 25 kg or above.

26. The eliglustat or a pharmaceutically acceptable salt thereof of any one of claims 23-25, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 42 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 15 kg to less than 25 kg.

27. The eliglustat or a pharmaceutically acceptable salt thereof of any one of claims 23-25, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs from 25 kg to less than 50 kg.

28. The eliglustat or a pharmaceutically acceptable salt thereof of any one of claims 23-25, wherein the therapeutically effective amount of eliglustat, or a pharmaceutically acceptable salt thereof is 84 mg twice per day if the pediatric patient is aged from 6 years to less than 18 years and weighs at least 50 kg.

29. The eliglustat or a pharmaceutically acceptable salt thereof of any one of claims 23-28, wherein the CYP2D6 genotyping has been performed by PCR or by microarray based testing.

30. The eliglustat or a pharmaceutically acceptable salt thereof of any one of claims 23-29, wherein the eliglustat, or pharmaceutically acceptable salt thereof is eliglustat hemitartrate.

31. The eliglustat or a pharmaceutically acceptable salt thereof of any one of claims 23-30, wherein the Gaucher disease is type 1 Gaucher disease.

32. The eliglustat or a pharmaceutically acceptable salt thereof of any one of claims-31, wherein the patient was previously treated with enzyme replacement therapy (ERT).

33. The eliglustat or a pharmaceutically acceptable salt thereof of any one of claims-32, wherein the patient is stable on enzyme replacement therapy (ERT).

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