Methods of treating fabry disease in patients having renal impairment

Abstract

To provide methods for treatment of Fabry disease in a patient having renal impairment.SOLUTION: Certain methods comprise administering to the patient about 100 mg to about 300 mg free base equivalent of migalastat or salt thereof at a frequency of greater than once every other day, such as once every four or seven days. Certain methods comprise measuring lyso-Gb3 and / or migalastat in one or more plasma samples from the patient.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Principles and embodiments of the present invention relate generally to the use of pharmacological chaperones for the treatment of Fabry disease, particularly in patients with varying degrees of renal impairment. [Background technology]

[0002] Many human diseases result from mutations that cause changes in the amino acid sequence of proteins, reducing their stability and preventing their proper folding. Proteins generally fold within a specific region of the cell known as the endoplasmic reticulum, or ER. Cells have quality control mechanisms that ensure proteins fold into their correct three-dimensional shape and then move from the ER to their appropriate destination within the cell, a process generally referred to as protein trafficking. Misfolded proteins are often initially retained in the ER and then eliminated by the quality control mechanisms. In some cases, misfolded proteins can accumulate in the ER before being eliminated. Retention of misfolded proteins in the ER can interfere with their proper trafficking, resulting in reduced biological activity and impairing cellular function, ultimately leading to disease. In addition, accumulation of misfolded proteins in the ER can cause various stresses on the cell, which can also contribute to cellular dysfunction and disease.

[0003] Such mutations can lead to lysosomal storage disorders (LSDs), characterized by lysosomal enzyme deficiencies due to mutations in genes encoding the lysosomal enzymes. The resulting disease causes pathological accumulation of the enzyme's substrates, including lipids, carbohydrates, and polysaccharides. While many different mutational genotypes exist associated with each LSD, many of these mutations are missense mutations that can lead to the production of less stable enzymes. These less stable enzymes are sometimes prematurely degraded by ER-associated degradation pathways, resulting in enzyme deficiencies in lysosomes and pathological accumulation of substrates. Such mutant enzymes are sometimes referred to in the art as "folding mutants" or "conformational mutants."

[0004] Fabry disease is a rare genetic disorder caused by mutations in the GLA gene, which encodes the enzyme α-galactosidase A (α-Gal A). α-Gal A is required for glycosphingolipid metabolism. This mutation leads to the accumulation of the substrate globotriaosylceramide (Gb3, GL-3, or ceramide trihexoside) in various tissues and organs. Because the disease gene is encoded on the X chromosome, males with Fabry disease are hemizygous. Fabry disease is estimated to affect 1 in 40,000 and 1 in 60,000 men, with a lower incidence in women.

[0005] Several approaches to treating Fabry disease exist. One approved therapy for Fabry disease is enzyme replacement therapy (ERT), which typically involves intravenous infusion of a purified form of the corresponding wild-type protein (Fabrazyme®, Genzyme Corp.). However, ERT has several drawbacks. One of the major complications of enzyme replacement therapy is the rapid degradation of the injected protein, which leads to multiple, expensive, high-dose infusions. ERT has several additional caveats, including the difficulty of large-scale production, purification, and storage of properly folded protein; the availability of glycosylated native protein; the development of anti-protein immune responses; and the inability of the protein to cross the blood-brain barrier and alleviate central nervous system pathology (i.e., low bioavailability). In addition, the replacement enzyme cannot penetrate the heart or kidney in sufficient quantities to reduce substrate accumulation in renal podocytes or cardiomyocytes, which is prominent in Fabry disease.

[0006] Another therapeutic approach for certain enzyme deficiencies involves the use of small molecule inhibitors to reduce the production of the defective enzyme protein's natural substrate, thereby alleviating the pathology. This "substrate inhibition" approach has been described specifically for a class of approximately 40 related enzyme disorders called lysosomal storage disorders, including glycosphingolipid storage disorders. The small molecule inhibitors proposed for use as therapy are specific for inhibiting enzymes involved in glycolipid synthesis, reducing the amount of cellular glycolipid that needs to be degraded by the defective enzyme.

[0007] A third approach to treating Fabry disease involves treatment with so-called pharmacological chaperones (PCs), which contain small molecule inhibitors of α-Gal A that can bind to α-Gal A and increase the stability of both the mutant enzyme and its wild-type counterpart.

[0008] One problem with current treatments is the difficulty in treating patients with renal impairment, which is extremely common in Fabry patients and progresses with the disease. On average, it takes approximately 10 to 20 years for patients to deteriorate from normal kidney function to severe kidney impairment, with even faster deterioration reported in some countries. According to some estimates, approximately 10% of Fabry patients receiving ERT may have moderate kidney impairment. An additional 25% of men and 5% of women receiving ERT have an estimated glomerular filtration rate (eGFR) below 30, corresponding to severe kidney impairment or even kidney failure. Of these, approximately half have severe kidney impairment and approximately half are on dialysis.

[0009] Unfortunately, kidney dysfunction will progress regardless of ERT treatment. Patients with an eGFR of 30 may progress to the point of needing dialysis within 2 to 5 years. Approximately 30% of patients receiving ERT will eventually require dialysis or a kidney transplant, depending on when ERT is initiated. Early initiation of ERT may preserve kidney function longer, but because Fabry disease is rare and often misdiagnosed, initiation of ERT may be delayed. Summary of the Invention [Problem to be solved by the invention]

[0010] Furthermore, and as discussed above, ERT often does not penetrate the kidney sufficiently to reduce substrate accumulation, thereby causing further damage during disease progression. In PC treatment, the kidney is often how drugs are removed from the body, and renal dysfunction can affect the pharmacokinetics and / or pharmacodynamics of drugs. Thus, there remains a need for treatments for Fabry patients with renal dysfunction. [Means for solving the problem]

[0011] One aspect of the present invention relates to a method for treating Fabry disease in a patient with impaired renal function, the method comprising administering to the patient about 100 mg to about 300 mg free base equivalent (FBE) of migalastat or a salt thereof less frequently than once every other day. In one or more embodiments, the patient has moderate renal impairment. In one or more embodiments, the patient has severe renal impairment. In some embodiments, the migalastat is in a solid dosage form. In one or more embodiments, the patient is administered about 123 mg FBE. In some embodiments, the patient is administered about 150 mg migalastat HCl. In one or more embodiments, the migalastat is administered orally. In one or more embodiments, the migalastat is administered for at least 28 days. In one or more embodiments, the migalastat is administered for at least 6 months. In one or more embodiments, the migalastat is administered for at least 12 months.

[0012] A second aspect of the present invention relates to a method for treating Fabry disease in a patient with impaired renal function, the method comprising administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every seven days. In some embodiments, the patient has moderate renal function impairment. In one or more embodiments, the patient has severe renal function impairment. In some embodiments, the migalastat is in a solid dosage form. In one or more embodiments, the patient is administered about 123 mg FBE. In some embodiments, the patient is administered about 150 mg migalastat HCl. In one or more embodiments, the migalastat is administered orally. In one or more embodiments, the migalastat is administered for at least 28 days. In one or more embodiments, the migalastat is administered for at least 6 months. In one or more embodiments, the migalastat is administered for at least 12 months.

[0013] A third aspect of the present invention relates to a method for treating Fabry disease in a patient with impaired renal function, comprising administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a first frequency of once every other day for a first period of time; and administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a second frequency of less than every other day for a second period of time. In one or more embodiments, the second frequency ranges from once every three days to once every seven days. In one or more embodiments, the second frequency is once every four days. In one or more embodiments, the second frequency is once every seven days. In one or more embodiments, administration at the second frequency begins after the patient's eGFR has declined. In one or more embodiments, the decline in eGFR is greater than or equal to 30 mL / min / 1.73 m 2 Above 30mL / min / 1.73m 2 or a decline in a patient's renal function from mild or moderate renal impairment to severe renal impairment.

[0014] In some embodiments, the method comprises: (a) measuring lyso-Gb3 in one or more plasma samples from the patient; (b) determining a first baseline lyso-Gb3 level during a first time period; (c) Migalastat concentration in one or more plasma samples from the patient during the first period, AUC 0-∞ and / or C. trough measuring; and (d) administering at a second frequency, (i) after a first increase above baseline lyso-Gb3 levels, and (ii) a migalastat level greater than about 5 ng / mL measured 48 hours after administration of migalastat during the first period, or an AUC 0-∞ and / or C. trough After a greater than 1.5-fold increase in To start Further includes:

[0015] In one or more embodiments, the method comprises: (a) measuring lyso-Gb3 in one or more plasma samples from the patient; (b) determining a first baseline lyso-Gb3 level during a first time period; (c) Migalastat concentration in one or more plasma samples from the patient during the first period, AUC 0-∞ and / or C. trough measuring; and (d) administering at a second frequency, (i) after a first increase above baseline lyso-Gb3 levels, and (ii) a migalastat level greater than about 5 ng / mL measured 48 hours after administration of migalastat during the first period, or an AUC 0-∞ and / or C. trough After a greater than 1.5-fold increase in To start Further includes:

[0016] In some embodiments, the increase over the first baseline lyso-Gb3 level is at least about 30% and / or 2 nM. In one or more embodiments, measuring migalastat includes measuring a migalastat concentration, and administration at the second frequency begins after measuring greater than about 10 ng / mL of migalastat 48 hours after administration of migalastat during the first period. In some embodiments, measuring migalastat includes measuring an AUC 0-∞ or C trough This involves measuring the AUC 0-∞ and / or C. trough In one or more embodiments, the second frequency is once every four days, and the method further comprises administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a third frequency of once every seven days for a third period of time.

[0017] In some embodiments, the method comprises: (a) measuring lyso-Gb3 in one or more plasma samples from the patient; (b) determining a first baseline lyso-Gb3 level during a first time period; (c) Migalastat concentration in one or more plasma samples from the patient during the first period, AUC 0-∞ and / or C. trough To measure; (d) administering at a second frequency, (i) after a first increase above baseline lyso-Gb3 levels, and (ii) a migalastat level greater than about 5 ng / mL measured 96 hours after administration of migalastat during the first time period, or an AUC 0-∞ and / or C. trough After a greater than 1.5-fold increase in To start with; (e) determining a second baseline lyso-Gb3 level during a second time period; and (f) administering at a third frequency, (i) after a second increase above baseline lyso-Gb3 levels, and (ii) a migalastat level greater than about 5 ng / mL is measured 48 hours after administration of migalastat during the second period, or an AUC 0-∞ and / or C. trough After a greater than 1.5-fold increase in To start Further includes:

[0018] In one or more embodiments, the increase over the first baseline lyso-Gb3 level is at least about 30% and / or 2 nM. In some embodiments, greater than about 10 ng / mL of migalastat is measured 48 hours after administration of migalastat during the first time period. In one or more embodiments, the second frequency is once every 7 days.

[0019] In some embodiments, the method comprises: (a) measuring lyso-Gb3 in one or more plasma samples from the patient; (b) determining a first baseline lyso-Gb3 level during a first time period; (c) Migalastat concentration in one or more plasma samples from the patient during the first period, AUC 0-∞ and / or C. trough measuring; and (d) administering at a second frequency, (i) after a first increase above baseline lyso-Gb3 levels, and (ii) a migalastat level greater than about 5 ng / mL measured 48 hours after administration of migalastat during the first period, or an AUC 0-∞ and / or C. trough After a greater than 1.5-fold increase in To start Further includes:

[0020] In one or more embodiments, the increase over the first baseline lyso-Gb3 level is at least about 30% and / or 2 nM. In some embodiments, greater than about 10 ng / mL of migalastat is measured 48 hours after administration of migalastat during the first period of time.

[0021] In one or more embodiments, the patient has moderate renal impairment. In some embodiments, the patient has severe renal impairment. In one or more embodiments, the migalastat is in a solid dosage form. In some embodiments, the patient is administered about 123 mg FBE. In one or more embodiments, the patient is administered about 150 mg migalastat HCl. In some embodiments, the migalastat is administered orally.

[0022] Another aspect of the invention relates to the use of migalastat in the treatment of Fabry disease in patients with impaired renal function, wherein the migalastat is administered to a patient with Fabry disease with impaired renal function in an amount of about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every four or seven days. In one or more embodiments, the frequency is once every four days. In some embodiments, the frequency is once every seven days. In one or more embodiments, the patient has moderate renal impairment. In some embodiments, the patient has severe renal impairment. In one or more embodiments, the migalastat is in a solid dosage form. In some embodiments, the patient is administered about 123 mg FBE. In one or more embodiments, the patient is administered about 150 mg migalastat HCl. In some embodiments, the migalastat is administered orally.

[0023] Various embodiments are listed below. It will be understood that the embodiments listed below are not limited to those listed below and may be combined in other suitable combinations within the scope of the present invention. [Brief explanation of the drawings]

[0024] [Figure 1A] Shows migalastat plasma concentrations as a function of CLCR in non-Fabry patients with various degrees of renal impairment; [Figure 1B] Shows migalastat plasma concentrations as a function of time post-dose in non-Fabry patients with various degrees of renal impairment; [Figure 1C] Migalastat area under the curve (AUC) is shown for non-Fabry patients with various degrees of renal impairment; [Figure 2] Figures 2A-2D show migalastat concentrations as a function of time for various dosing regimens and degrees of renal dysfunction; [Figure 3] Figures 3A-3B show the accumulation ratios and migalastat concentrations for various dosing regimens; [Figure 4]Migalastat AUC0-∞ and 48-hour migalastat concentrations as a function of non-Fabry patients with varying degrees of renal impairment; [Figure 5] Plasma migalastat concentrations at 48 hours as a function of eGFRMDRD in non-Fabry patients with various degrees of renal impairment and two Fabry patients with renal impairment; [Figure 6] Plasma migalastat AUC0-∞ is shown for non-Fabry patients with various degrees of renal impairment and two Fabry patients with renal impairment; [Figures 7A-7D] Simulated median and observed migalastat concentrations over time for normal, severe, mild, and moderately impaired renal subjects, respectively; [Figures 8A-8D] Migalastat Cmax, AUC, Cmin and C48h in normal, mild, moderate and severe renal impairment subjects, respectively; [Figures 9A-9D] Shown are steady-state predictions of QOD for normal, severe, mild and moderate renal impairment subjects, respectively; [Figures 10A-10D] Migalastat Cmax, AUC, Cmin and C48h are shown for normal, mild, moderate and severe renal impairment subjects, respectively; [Figure 11A] Shows migalastat concentrations over 96 hours after administration of 100 mg migalastat in patients with moderate renal impairment; [Figure 11B] Shows migalastat concentrations over 48 hours after administration of 150 mg migalastat in patients with normal renal function; [Figure 12] Figures 12A-12D show migalastat Cmax, AUC, Cmin and C48h for normal and moderately renal impaired subjects, respectively; [Figure 13A] Figure 13A shows the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1); [Figure 13B] Figure 13B shows the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1); [Figure 13C] Figure 13C shows the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1); [Figure 13D] Figure 13D shows the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1); [Figure 13E] Figure 13E shows the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1); [Figure 14] shows the wild-type GLA protein (SEQ ID NO: 2); and [Figure 15] 1 shows lyso-Gb3 and eGFR over time for patient P3. DETAILED DESCRIPTION OF THE INVENTION

[0025] Before describing several exemplary embodiments of the invention, it is to be understood that the invention is not limited to the details of construction or method steps set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0026] Various aspects of the present invention relate to specific migalastat dosing regimens, or salts thereof, for Fabry patients with impaired renal function. Migalastat is a pharmacological chaperone used to treat Fabry disease. This pharmacological chaperone is normally cleared from the body by the kidneys. However, patients with impaired renal function (a common problem in Fabry patients) may be unable to clear migalastat from the body, and it has previously been unknown how patients with both Fabry disease and impaired renal function might respond to migalastat therapy. Because pharmacological chaperones are also inhibitors, balancing the enzyme-enhancing and inhibitory effects of pharmacological chaperones, such as migalastat, is extremely challenging. Furthermore, due to the complex interactions between Fabry disease and renal function and the lack of knowledge regarding the role of pharmacological chaperones, dosing of migalastat for Fabry patients with impaired renal function is difficult to ascertain without available clinical data and / or computer modeling.

[0027] Accordingly, one aspect of the present invention relates to a method for treating Fabry disease in a patient with impaired renal function. In an exemplary embodiment, the method comprises administering migalastat or a salt thereof every 2, 3, 4, 5, 6, or 7 days. Although administration every 4 or 7 days is specifically mentioned, the methods and uses disclosed herein can also be used with other intermittent administration regimens, such as every 3, 5, or 6 days, based on, for example, the patient's renal condition.

[0028] In one or more embodiments, the method comprises administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every four days. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every seven days. In some embodiments, the method comprises administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every four days for a first period of time, and then administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every seven days for a second period of time. The patient may have mild, moderate, or severe renal impairment.

[0029] Another aspect of the present invention relates to the use of migalastat in the treatment of Fabry disease in patients with renal impairment, wherein migalastat is administered to a patient with Fabry disease with renal impairment in an amount of about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every 4 or 7 days. The patient can have mild, moderate, or severe renal impairment. In one or more embodiments, the patient has moderate or severe renal impairment. In a specific embodiment, the patient has moderate renal impairment. In another specific embodiment, the patient has severe renal impairment.

[0030] definition The terms used herein generally have their ordinary meaning in the art, within the context of this invention and in the specific context in which each term is used. Certain terms are discussed below or elsewhere in this specification to provide further guidance to the practitioner in describing the compositions and methods of the invention and how to make and use them.

[0031] The term "Fabry disease" refers to an X-linked congenital abnormality of glycosphingolipid catabolism caused by deficient activity of lysosomal α-galactosidase A. This defect leads to the accumulation of globotriaosylceramide (ceramide trihexoside) and related glycosphingolipids in vascular endothelial lysosomes in the heart, kidney, skin, and other tissues.

[0032] The term "atypical Fabry disease" refers to patients who have primarily cardiac manifestations of α-Gal A deficiency, i.e., progressive globotriaosylceramide (GL-3) accumulation in cardiomyocytes leading to marked enlargement of the heart, particularly the left ventricle.

[0033] A "carrier" is a female in whom one X chromosome contains a defective α-Gal A gene and one X chromosome contains a normal gene, and in which there is X chromosome inactivation of the normal allele in one or more cell types. Carriers are often diagnosed with Fabry disease.

[0034] "Patient" refers to a subject who has been diagnosed with or is suspected of having a particular disease. The patient may be a human or an animal.

[0035] "Fabry disease patient" refers to an individual with mutant α-Gal A, as further defined below, who has been diagnosed with or is suspected of having Fabry disease. The hallmark markers for Fabry disease can appear with equal prevalence in hemizygous male and female carriers, although females are typically affected with less severe disease.

[0036] Human α-galactosidase A (α-Gal A) refers to the enzyme encoded by the human GLA gene. The complete DNA sequence of α-Gal A, including introns and exons, is available under GenBank accession number X14448.1 and is shown in SEQ ID NO: 1 and Figures 13A-13E. The human α-Gal A enzyme consists of 429 amino acids and is available under GenBank accession numbers X14448.1 and U78027.1, and is shown in SEQ ID NO: 2 and Figure 14.

[0037] The term "mutant protein" includes proteins that have a mutation in the gene encoding the protein that prevents the protein from achieving a stable conformation under conditions normally present in the ER. Failure to achieve a stable conformation results in significant amounts of the enzyme not being transported to lysosomes but rather being degraded. Such mutations are sometimes referred to as "conformational mutants." Such mutations include, but are not limited to, missense mutations and small in-frame deletions and insertions.

[0038] As used herein in one embodiment, the term "mutant α-Gal A" includes α-Gal A with a mutation in the gene encoding α-Gal A that prevents the enzyme from achieving a stable conformation under conditions normally present in the ER. The inability to achieve a stable conformation results in significant amounts of the enzyme not being transported to lysosomes but rather being degraded.

[0039] As used herein, the term "specific pharmacological chaperone" ("SPC") or "pharmacological chaperone" ("PC") refers to any molecule, including small molecules, proteins, peptides, nucleic acids, carbohydrates, etc., that specifically binds to a protein and has one or more of the following effects: (i) promoting the formation of a stable molecular conformation of the protein; (ii) directing trafficking of the protein from the ER to another cellular site, preferably the native cellular site, i.e., preventing ER-associated degradation of the protein; (iii) preventing aggregation of misfolded proteins; and / or (iv) restoring or enhancing at least some wild-type function and / or activity to a protein. For example, a compound that specifically binds to α-Gal A means that it binds to and exerts a chaperone effect on that enzyme and not on a general group of related or unrelated enzymes. More specifically, the term does not refer to endogenous chaperones such as BiP, or nonspecific agents, i.e., chemical chaperones, that demonstrate nonspecific chaperone activity for a variety of proteins, such as glycerol, DMSO, or heavy water. In one or more embodiments of the invention, the PC may be a reversible competitive inhibitor.

[0040] A "competitive inhibitor" of an enzyme can refer to a compound that is structurally similar to the chemical and molecular structure of the enzyme substrate and binds to the enzyme at approximately the same location as the substrate. Thus, the inhibitor competes for the same active site as the substrate molecule, thus increasing the Km. Competitive inhibition is usually reversible if enough substrate molecules are available to displace the inhibitor; i.e., competitive inhibitors can bind reversibly. Therefore, the amount of enzyme inhibition depends on the inhibitor concentration, the substrate concentration, and the relative affinities of the inhibitor and substrate for the active site.

[0041] As used herein, the term "specifically binds" refers to the interaction of a pharmacological chaperone with a protein, such as α-Gal A, specifically with amino acid residues in the protein that are directly involved in contact with the pharmacological chaperone. A pharmacological chaperone specifically binds to a target protein, e.g., α-Gal A, and exerts a chaperone effect on that protein, rather than on a general group of related or unrelated proteins. The amino acid residues in a protein that interact with a given pharmacological chaperone may or may not be within the "active site" of the protein. Specific binding can be assessed by routine binding assays or by structural studies, e.g., cocrystallization, NMR, etc. The active site of α-Gal A is the substrate-binding site.

[0042] "Deficient α-Gal A activity" refers to α-Gal A activity in cells from a patient that is below the normal range when compared (using the same method) with the activity of normal individuals who do not have or are not suspected of having Fabry disease or any other disease (particularly a hematological disorder).

[0043] As used herein, the terms "enhancing α-Gal A activity" or "increasing α-Gal A activity" refer to increasing the amount of α-Gal A in a stable conformation in cells contacted with an α-Gal A-specific pharmacological chaperone compared to the amount in cells (preferably of the same cell type, or the same cells, e.g., at an earlier stage) that have not been contacted with the α-Gal A-specific pharmacological chaperone. The terms also refer to increasing α-Gal A trafficking to lysosomes in cells contacted with an α-Gal A-specific pharmacological chaperone compared to trafficking of α-Gal A not contacted with a pharmacological chaperone specific for that protein. These terms refer to both wild-type and mutant α-Gal A. In one embodiment, the increase in α-Gal A amount in cells is measured by measuring the hydrolysis of an artificial substrate in lysates from cells treated with PC. Increased hydrolysis is an indication of increased α-Gal A activity.

[0044] The term "α-Gal A activity" refers to the normal physiological function of wild-type α-Gal A in a cell. For example, α-Gal A activity includes the hydrolysis of GL-3.

[0045] A "responder" is an individual diagnosed with or suspected of having a lysosomal storage disorder, e.g., Fabry disease, whose cells respond to contact with PC by exhibiting a sufficient increase in α-Gal A activity and / or symptomatic relief or improvement in surrogate markers, respectively. Non-limiting examples of improvement in Fabry surrogate markers include lyso-Gb3 and those disclosed in U.S. Patent Application Publication No. 2010-0113517, hereby incorporated by reference in its entirety.

[0046] Non-limiting examples of improved surrogate markers for Fabry disease disclosed in U.S. Patent Application Publication No. 2010 / 0113517 include the detection of α-Gal in cells (e.g., fibroblasts) and tissues. These include increased Aβ levels or activity, decreased GL-3 accumulation, decreased plasma concentrations of homocysteine ​​and vascular cell adhesion molecule-1 (VCAM-1), decreased GL-3 accumulation in cardiomyocytes and valvular fibrocytes, decreased plasma globotriaosylsphingosine (lyso-Gb3), decreased cardiac hypertrophy (especially the left ventricle), valvular insufficiency, and arrhythmias, reduced proteinuria, decreased urinary concentrations of lipids such as CTH, lactosylceramide, and ceramide, and increased urinary concentrations of glucosylceramide and sphingomyelin, no lamellar inclusion bodies (zebra bodies) in glomerular epithelial cells, improved renal function, reduced hypohidrosis, no angiokeratoma, and improvement in hearing abnormalities such as high-frequency sensorineural hearing loss, progressive hearing loss, sudden hearing loss, or tinnitus. Improvements in neurological symptoms include prevention of transient ischemic attacks (TIA) or stroke, and relief of neuropathic pain manifesting as acroparesthesia (burning or tingling pain in the extremities). Another clinical marker that may be diagnostic of Fabry disease is the prevalence of adverse cardiovascular symptoms. Common cardiac signs and symptoms in Fabry disease include left ventricular hypertrophy, valvular disease (especially mitral valve prolapse and / or regurgitation), premature coronary artery disease, angina, myocardial infarction, conduction abnormalities, arrhythmias, and congestive heart failure.

[0047] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and typically do not produce adverse reactions when administered to humans. In some embodiments, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency for use in animals, more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia. With respect to pharmaceutical carriers, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Such pharmaceutical carriers may be sterile liquids, such as water and oils. Water or aqueous solutions, saline solutions, and aqueous dextrose and glycerol solutions are preferably utilized as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 18th Edition, or other editions.

[0048] The term "enzyme replacement therapy" or "ERT" refers to the introduction of a non-native purified enzyme into an individual deficient in such an enzyme. The administered protein may be obtained from a natural source or by recombinant expression (as described in more detail below). The term also refers to the introduction of a purified enzyme in an individual who would otherwise require or benefit from the administration of the purified enzyme, e.g., an individual suffering from an enzyme deficiency. The introduced enzyme may be a purified recombinant enzyme made in vitro, or may be a protein purified from isolated tissue or body fluids, such as placenta or animal milk, or purified from a plant.

[0049] As used herein, the term "isolated" means that the referenced material is removed from the environment in which it is normally found. Thus, isolated biological material can be free of cellular components, i.e., components of the cells in which the material is found or produced. In the case of nucleic acid molecules, isolated nucleic acids include PCR products, mRNA bands on gels, cDNA, or restriction fragments. In another embodiment, isolated nucleic acids are preferably excised from the chromosome in which they are found, and more preferably, when found in a chromosome, they are no longer connected to non-regulatory regions, non-coding regions, or other genes located upstream or downstream of the gene contained in the isolated nucleic acid molecule. In yet another embodiment, isolated nucleic acids lack one or more introns. Isolated nucleic acids include sequences inserted into plasmids, cosmids, artificial chromosomes, etc. Thus, in a specific embodiment, recombinant nucleic acids are isolated nucleic acids. An isolated protein may be associated with other proteins or nucleic acids, or both, with the cell to which it is associated, or, if it is a membrane-bound protein, with the cell membrane. An isolated organelle, cell, or tissue is removed from the anatomical site in an organism in which it is found. An isolated material may, but need not, be purified.

[0050] The terms "about" and "approximately" are generally intended to refer to an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. Typical exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, particularly in biological systems, the terms "about" and "approximately" can refer to values ​​within an order of magnitude of a given value, preferably within 10-fold or 5-fold, and more preferably within 2-fold. Numerical quantities provided herein are approximate unless otherwise specified, i.e., the terms "about" or "approximately" can be implied even when not explicitly stated.

[0051] As used herein, the term "free base equivalent" or "FBE" refers to the amount of migalastat present in migalastat or a salt thereof. In other words, the term "FBE" refers to either the amount of migalastat free base or the equivalent amount of migalastat free base provided by a salt of migalastat. For example, due to the weight of the hydrochloride salt, only 150 mg of migalastat hydrochloride provides the same amount of migalastat as 123 mg of migalastat in free base form. Other salts are expected to have different conversion factors depending on the molecular weight of the salt.

[0052] The term "migalastat" includes migalastat free base or a pharmaceutically acceptable salt thereof (eg, migalastat HCl), unless specifically indicated to the contrary.

[0053] Fabry disease Fabry disease is a rare, progressive, severe, X-linked lysosomal storage disorder. Mutations in the GLA gene cause a deficiency of the lysosomal enzyme α-Gal A, which is required for glycosphingolipid metabolism. Decreased α-Gal A activity, which begins in early childhood, leads to the accumulation of glycosphingolipids, including GL-3 and plasma lyso-Gb3, leading to the symptoms and fatal sequelae of Fabry disease, including pain, gastrointestinal symptoms, renal failure, cardiomyopathy, cerebrovascular events, and premature death. Early initiation of therapy and lifelong treatment offers the opportunity to slow disease progression and extend life expectancy.

[0054] Fabry disease encompasses a range of disease severity and age of onset, but is traditionally divided into two major phenotypes, "classic" and "late-onset." The classic phenotype is primarily considered to be in men with undetectable to low α-Gal A activity and early onset of renal, cardiac, and / or cerebrovascular symptoms. The late-onset phenotype is primarily considered to be in men with higher residual α-Gal A activity and later onset of these disease symptoms. Heterozygous female carriers typically express the late-onset phenotype, but may also exhibit the classic phenotype depending on the pattern of X-chromosome inactivation.

[0055] Over 800 GLA mutations responsible for Fabry disease have been identified. Approximately 60% are missense mutations resulting in a single amino acid substitution in the α-Gal A enzyme. Missense GLA mutations often result in the production of abnormally folded, unstable forms of α-Gal A, the majority of which are associated with the classic phenotype. Normal cellular quality control mechanisms in the endoplasmic reticulum prevent these abnormal proteins from trafficking to lysosomes, targeting them for premature degradation and removal. Many missense mutant forms are targets of migalastat, an α-Gal A-specific pharmacological chaperone.

[0056] The clinical manifestations of Fabry disease range in severity and roughly correlate with a patient's residual α-GAL levels. The majority of patients currently receiving treatment are referred to as patients with classic Fabry disease, most of whom are men. These patients experience disease in various organs, including the kidneys, heart, and brain. Disease symptoms first appear in adolescence and progress in severity until death, typically in the patient's 30s or 40s. Several recent studies suggest that there are many undiagnosed men and women with various Fabry disease symptoms, such as cardiac or renal dysfunction and stroke, that usually first appear in adulthood. This type of Fabry disease, referred to as late-onset Fabry disease, tends to have higher residual α-GAL levels than patients with classic Fabry disease. Late-onset Fabry disease patients typically experience their first disease symptoms in adulthood and often have disease symptoms localized to a single organ, such as left ventricular hypertrophy or progressive renal failure. In addition, late-onset Fabry disease can also present as stroke of unknown etiology.

[0057] Patients with Fabry disease have progressive renal dysfunction, and untreated individuals develop end-stage renal disease by their fourth decade. Deficiency of α-Gal A activity leads to the accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in many cell types, including those of the kidney. Gb3 accumulates in podocytes, distal tubules, and epithelial and tubular cells of the loop of Henle. Renal dysfunction can manifest as proteinuria and a reduced glomerular filtration rate.

[0058] Because Fabry disease can cause progressive deterioration of renal function, it is important to understand the pharmacokinetics (PK) of potential therapeutic agents in renal impairment, especially for agents that are primarily eliminated by renal excretion. Impaired renal function can lead to the accumulation of therapeutic agents to toxic levels.

[0059] Proper diagnosis of Fabry disease is challenging due to its rarity, multiorgan involvement, wide age range of onset, and heterogeneity. Misdiagnosis is frequent due to low awareness among medical professionals. The diagnosis of Fabry disease is most often confirmed after a patient presents with symptoms, based on reduced α-Gal A activity in plasma or peripheral white blood cells (WBCs) in conjunction with mutation analysis. Diagnosis is even more challenging in females, due to unreliable enzymatic identification of carrier females due to random X-chromosome inactivation in some carrier cells. For example, some obligate carriers (daughters of classically affected men) have α-Gal A enzyme activity ranging from normal to very low activity. Because carriers may have normal α-Gal A enzyme activity in white blood cells, only identification of the α-Gal A mutation by genetic testing provides accurate carrier identification and / or diagnosis.

[0060] A mutant form of α-galactosidase A that is considered migalastat applicable is defined as one that exhibits a ≥ 1.20-fold relative increase (+10 μM migalastat) and a ≥ 3.0% absolute increase (+10 μM migalastat) over wild-type (WT) when the mutant form of α-galactosidase A is expressed in HEK-293 cells according to a Good Laboratory Practice (GLP) validated in vitro assay (GLP HEK or migalastat applicability assay) (referred to as the "HEK assay"). Such mutations are also referred to herein as "HEK assay applicable" mutations.

[0061] Prior screening methods have been provided to determine enzyme enhancement before treatment begins. For example, an assay using HEK-293 cells has been utilized in clinical trials to predict whether a given mutation will respond to pharmacological chaperone (e.g., migalastat) treatment. In this assay, a cDNA construct is generated. The corresponding α-Gal A mutant form is transiently expressed in HEK-293 cells. The cells are then incubated with migalastat (17 nM to 1 mM) for 4 to 5 days. α-Gal A levels are then measured in cell lysates using a synthetic fluorogenic substrate (4-MU-α-Gal) or by Western blot. This has been performed for known disease-causing missense or small in-frame insertion / deletion mutations. Mutations previously identified as responsive to PC (e.g., migalastat) using these methods are listed in U.S. Patent No. 8,592,362 (hereby incorporated by reference in their entirety).

[0062] Pharmacological Chaperones Binding of small molecule inhibitors of LSD-related enzymes can increase the stability of both mutant and corresponding wild-type enzymes (see U.S. Patent Nos. 6,274,597; 6,583,158; 6,589,964; 6,599,919; 6,916,829; and 7,141,582, all of which are incorporated herein by reference). Specifically, administration of small molecule derivatives of glucose and galactose, which are specific and selective competitive inhibitors of several target lysosomal enzymes, effectively increased the stability of the enzymes in cells in vitro, thereby increasing the trafficking of the enzymes to lysosomes. Therefore, increasing the amount of enzymes in lysosomes is expected to increase the hydrolysis of the enzyme substrates. The original theory behind this strategy was as follows: Because mutant enzyme proteins are unstable in the ER (Ishii et al., Biochem. Biophys. Res. Comm. 1996;220:812-815), they are delayed in their normal transport pathway (ER → Golgi apparatus → endosomes → lysosomes) and are prematurely degraded. Therefore, compounds that bind to and increase the stability of mutant enzymes could act as "chaperones" for the enzymes, increasing the amount that can exit the ER and be transported to lysosomes. In addition, because folding and trafficking of some wild-type proteins are incomplete, and in some cases up to 70% of some wild-type proteins are degraded before reaching their final cellular location, chaperones could be used to stabilize wild-type enzymes, increasing the amount of enzyme that can exit the ER and be transported to lysosomes.

[0063] In one or more embodiments, the pharmacological chaperone comprises migalastat or a salt thereof. The compound migalastat, also known as 1-deoxygalactonojirimycin (1-DGJ) or (2R,3S,4R,5S)-2-(hydroxymethyl)piperdine-3,4,5-triol, is a compound having the following chemical formula: [ka]

[0064] As discussed herein, pharmaceutically acceptable salts of migalastat may also be used in the present invention. When a salt of migalastat is used, the dosage of the salt will be adjusted so that the patient receives a dose of migalastat equivalent to the amount that they would have received if migalastat free base had been used. An example of a pharmaceutically acceptable salt of migalastat is migalastat HCl: [ka]

[0065] Migalastat is a low-molecular-weight iminosugar and an analog of the terminal galactose of GL-3. In vitro and in vivo pharmacological studies have demonstrated that migalastat acts as a pharmacological chaperone, binding with high affinity, selectivity, and reversibility to the active site of wild-type (WT) α-Gal A and specific mutant forms of α-Gal A (these genotypes are referred to as HEK assay-compatible mutations). Upon binding, migalastat stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum, promoting their proper trafficking to lysosomes, where its dissociation allows α-Gal A to reduce levels of GL-3 and other substrates. Approximately 30-50% of patients with Fabry disease have HEK assay-compatible mutations; the majority of these are associated with the classic phenotype of the disease. The list of HEK assay-compatible mutations includes at least those listed in Table 1 below. In one or more embodiments, when double mutations are present on the same chromosome (male and female), the patient is considered eligible for the HEK assay if the double mutations are present in one entry in Table 1 (e.g., D55V / Q57L). In some embodiments, when double mutations are present on different chromosomes (females only), the patient is considered eligible for the HEK assay if either of the individual mutations are present in Table 1. In addition to Table 1 below, HEK assay eligible mutations can also be found in the GALAFOLD™ Summary of Product Characteristics and / or Prescribing Information in the various countries in which GALAFOLD™ is approved for use, or on the website www.galafoldamenabilitytable.com (each of which is hereby incorporated by reference in its entirety).

[0066] [Table 1]

[0067] [Table 2]

[0068]

Table 3

[0069]

Table 4

[0070]

Table 5

[0071]

Table 6

[0072]

Table 7

[0073]

Table 8

[0074]

Table 9

[0075]

Table 10

[0076]

Table 11

[0077]

Table 12

[0078]

Table 13

[0079]

Table 14

[0080]

Table 15

[0081] Table 16

[0082]

Table 17

[0083]

Table 18

[0084] Table 19

[0085] Table 20

[0086] Table 21

[0087] Table 22

[0088] Table 23

[0089] Table 24

[0090] Table 25

[0091] Table 26

[0092] Table 27

[0093] Table 28

[0094] Table 29

[0095]

Table 30

[0096] Table 31

[0097] Table 32

[0098]

Table 33

[0099] Table 34

[0100] Table 35

[0101] Table 36

[0102] Table 37

[0103] Table 38

[0104] Table 39

[0105] Table 40

[0106] Table 41

[0107] Table 42

[0108] Table 43

[0109] Table 44

[0110] [Table 45]

[0111] [Table 46]

[0112] [Table 47]

[0113] [Table 48]

[0114] [Table 49]

[0115] [Table 50]

[0116] [Table 51]

[0117] Renal function in Fabry patients Progressive deterioration of renal function is a major complication of Fabry disease. For example, patients associated with the classic Fabry phenotype present with progressive renal dysfunction that may lead to dialysis or kidney transplantation.

[0118] A commonly used method in the art for assessing renal function is GFR. Generally, GFR is the volume of fluid filtered from the glomerular capillaries into Bowman's capsule per unit time. In clinical practice, GFR is estimated based on the clearance of creatinine from serum. Estimated glomerular filtration rate (GFR) can be estimated by collecting urine and determining the amount of creatinine removed from the blood over a given time interval. Age, body size, and gender may also be included as factors. The lower the GFR number, the more advanced the kidney damage.

[0119] Some studies have shown that untreated Fabry patients have an average of 7.0 to 18.9 mL / min / 1.73 m per year. 2 patients on enzyme replacement therapy (ERT) experienced a worsening of GFR of 2.0–2.7 mL / min / 1.73 m per year on average. 2 It has been noted that patients with urinary tract infections may experience a worsening of GFR, although more rapid deterioration may occur in patients with more severe proteinuria or more severe chronic kidney disease. Therefore, even in patients receiving therapy, the appropriate dose of the therapeutic agent must be determined to take into account the progression of the patient's renal dysfunction. Dose adjustments can be used to avoid accumulation of the therapeutic agent to a level that falls outside the therapeutic index or where the patient experiences toxicity.

[0120] Estimated GFR (eGFR) is calculated from serum creatinine using an isotope dilution mass spectrometry (IDMS) traceable formula. Two of the most commonly used formulas for estimating glomerular filtration rate (GFR) from serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and the Modification of Diet in Renal Disease (MDRD) formula. Both the MDRD and CKD-EPI formulas include variables for age, sex, and race, which may allow providers to observe the presence of CKD despite serum creatinine levels appearing to be within or only slightly above the normal reference range.

[0121] The CKD-EPI equation uses two slope "splines" to model the relationship between GFR and serum creatinine, age, sex, and race. The CKD-EPI equation is expressed as a single equation: GFR = 141 × min(S cr / κ,1)α×max(S cr / κ,1)-1.209×0.993 年齢 × 1.018 [for women] × 1.159 [for black people] During the ceremony: S cr is serum creatinine in mg / dL, Kappa is 0.7 for women and 0.9 for men, Alpha was −0.329 for women and −0.411 for men, min is S cr / κ is the minimum value or 1, and max is S cr / κ indicates the maximum value or 1.

[0122] Below is the IDMS traceable MDRD research formula (for the creatinine method calibrated to the IDMS reference method): GFR (mL / min / 1.73m 2 )=175×(S cr ) -1.154 ×(age) -0.203 × (0.742 for women) × (1.212 for African Americans)

[0123] This formula is based on the commonly accepted average adult body surface area of ​​1.73 m 2 Results are reported normalized to body surface area, eliminating the need for weight or height variables. This formula is applicable to patients aged 18 to 70 years with impaired renal function (eGFR < 60 mL / min / 1.73 m). 2 ) It has been well validated in Caucasian and African American populations and has shown good performance in patients with all common causes of kidney disease.

[0124] Creatinine clearance rate (eCCr One way to estimate GFR is to use the Cockcroft-Gault formula, which in turn estimates GFR in mL / min: Creatinine clearance (mL / min) = [(140 - age) x weight (kg)] * ] ÷ 72 × serum creatinine (mg / dL) [ * For women, multiply by 0.85]

[0125] The Cockcroft-Gault formula is recommended by the Food and Drug Administration for use in studies of renal dysfunction. Creatinine clearance calculated by the Cockcroft-Gault formula is 1.73 m 2 It is common to normalize by body surface area. Therefore, this formula is mL / min / 1.73m 2 It can be expressed as an estimated eGFR in units of 1. The normal range for GFR adjusted for body surface area is 100-130 mL / min / 1.73 m² for men younger than 40 years and 90-120 mL / min / 1.73 m² for women.

[0126] The severity of chronic kidney disease is defined into six stages (see also Table 2): (Stage 0) Normal kidney function - GFR 90 mL / min / 1.73 m 2 and no proteinuria; (Stage 1) - GFR 90 mL / min / 1.73 m 2 and evidence of kidney damage; (Stage 2) (Mild) - GFR 60-89 mL / min / 1.73 m 2 and evidence of kidney damage; (Stage 3) (Moderate) - GFR 30-59 mL / min / 1.73 m 2 Stage 4 (Severe) - GFR is 15-29 mL / min / 1.73 m 2 (Stage 5) Renal failure - GFR 15 mL / min / 1.73 m 2 Table 2 below shows the various kidney disease stages with corresponding GFR levels.

[0127] [Table 52]

[0128] Dosing, Formulation and Administration One or more of the dosing regimens described herein are particularly suitable for Fabry patients with some degree of renal impairment. Amicus Therapeutics sponsored two Phase 3 trials using migalastat 150 mg every other day (QOD) in Fabry patients. FACETS (011, NCT00925301) was a 24-month trial with a 6-month double-blind, placebo-controlled period in 67 enzyme replacement therapy (ERT)-naive patients. ATTRACT (012, NCT01218659) was an 18-month, active-controlled trial in 57 ERT-experienced patients with a 12-month open-label extension (OLE). Both the FACETS and ATTRACT studies included patients with an estimated glomerular filtration rate (eGFR) of 30 mL / min / 1.73 m 2 Thus, both studies included Fabry patients with normal renal function and patients with mild and moderate renal impairment, but neither study included patients with severe renal impairment.

[0129] A phase 3 study of migalastat treatment in Fabry patients established that 150 mg every other day slowed disease progression as indicated by surrogate markers. However, in some embodiments, some Fabry patients may experience renal deterioration, and the migalastat dosing regimen may be adjusted for these patients. As the body's ability to clear the drug slows, patients' exposure to the drug may increase. Therefore, in some embodiments, a dose adjustment protocol is provided to inform physicians about the best dose, taking into account the current body's clearance profile. Dose adjustment is particularly challenging with chaperones, because they are inhibitors and must achieve a delicate balance of being present in sufficient amounts to have a therapeutic effect, but not so much that they inhibit enzyme function (which could worsen the disease). Therefore, predicting the correct dose is difficult, and this is further complicated in patients with reduced migalastat clearance.

[0130] Thus, in one or more embodiments, a Fabry patient with impaired renal function is administered about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every other day, once every three days, once every four days, once every five days, once every six days, or once every seven days. In one or more embodiments, migalastat or a salt thereof is administered once every other day (also referred to as "QOD" or "Q48H"), every four days (also referred to as "Q4D" or "Q96H"), or every seven days (also referred to as "Q7D" or "Q168H"). In some embodiments, a Fabry patient with impaired renal function is administered about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every four days. In other embodiments, a Fabry patient with impaired renal function is administered about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every seven days. In some embodiments, following or as a correction to a dosing regimen of about 100 mg to about 300 mg FBE of migalastat or a salt thereof once every other day, a dosing regimen with longer intervals (e.g., every 3 days to every 7 days) may be initiated.

[0131] In various embodiments, the doses described herein relate to migalastat hydrochloride or equivalent doses of migalastat or salts thereof other than the hydrochloride salt. In some embodiments, these doses relate to the free base of migalastat. In alternative embodiments, these doses relate to a salt of migalastat. In further embodiments, the salt of migalastat is migalastat hydrochloride. The administration of migalastat or a salt of migalastat is referred to herein as "migalastat therapy."

[0132] An effective amount of migalastat or a salt thereof can range from about 100 mg FBE to about 300 mg FBE. Exemplary doses include about 100 mg FBE, about 105 mg FBE, about 110 mg FBE, about 115 mg FBE, about 120 mg FBE, about 123 mg FBE, about 125 mg FBE, about 130 mg FBE, about 135 mg FBE, about 140 mg FBE, about 145 mg FBE, about 150 mg FBE, about 155 mg FBE, about 160 mg FBE, about 165 mg FBE, about 170 mg FBE, about 175 mg FBE, about 180 mg FBE, about 185 mg FBE, about 190 mg FBE, about 195 mg FBE, about 200 mg FBE, about 205 mg FBE, about 210 mg FBE, about 215 mg FBE, about 220 mg FBE, about 225 mg FBE, about 230 mg FBE, about 235 mg FBE, about 240 mg FBE, about 245 mg FBE, about 250 mg FBE, about 255 mg FBE, about 260 mg FBE, about 265 mg FBE, about 270 mg FBE, about 275 mg FBE, about 280 mg FBE, about 285 mg FBE, about 290 mg FBE, about 295 mg FBE, or about 300 mg FBE.

[0133] It is again noted that 150 mg of migalastat hydrochloride is equivalent to 123 mg of the free base form of migalastat. Thus, in one or more embodiments, the dose is 150 mg of migalastat hydrochloride administered once every other day, or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt. As indicated above, this dose is referred to as 123 mg FBE of migalastat. In a further embodiment, the dose is 150 mg of migalastat hydrochloride administered once every other day. In other embodiments, the dose is 123 mg of migalastat free base administered once every other day.

[0134] In various embodiments, an effective amount is about 122 mg, about 128 mg, about 134 mg, about 140 mg, about 146 mg, about 150 mg, about 152 mg, about 159 mg, about 165 mg, about 171 mg, about 177 mg, about 183 mg, about 189 mg, about 195 mg, about 201 mg, about 207 mg, about 213 mg, about 220 mg, about 226 mg, about 232 mg, about 238 mg , about 244 mg, about 250 mg, about 256 mg, about 262 mg, about 268 mg, about 274 mg, about 280 mg, about 287 mg, about 293 mg, about 299 mg, about 305 mg, about 311 mg, about 317 mg, about 323 mg, about 329 mg, about 335 mg, about 341 mg, about 348 mg, about 354 mg, about 360 mg or about 366 mg of migalastat hydrochloride.

[0135] Thus, in one or more embodiments, the dose is 150 mg migalastat hydrochloride administered every four days or every seven days, or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt. In further embodiments, the dose is 150 mg migalastat hydrochloride administered every four days. In other embodiments, the dose is 150 mg migalastat hydrochloride administered every seven days. In other embodiments, the dose is 123 mg migalastat free base administered every other day, every four days, or every seven days. With more severe renal impairment, longer dosing intervals (e.g., every 3-7 days) may be useful compared to an every other day dosing frequency. Such longer dosing intervals include every 3, 4, 5, 6, or 7 days.

[0136] In some embodiments, the dosing interval can include any dosing interval greater than 48 hours between doses. For example, the dosing interval can include dosing every 72, 96, 120, 144, or 168 hours.

[0137] In some embodiments, the dosing interval can include administration less than 3.5 times per week on average. For example, administration can be 3 times per week, 2 times per week, or once per week on average. In some embodiments, administration can be about 2.3 times per week or less, about 1.75 times per week or less, about 1.4 times per week or less, or about 1.167 times per week or less on average.

[0138] In some embodiments, the dosing intervals can be irregular. For example, the dosing intervals can include dosing every Monday, Wednesday, and Friday, but not on Tuesday, Thursday, Saturday, or Sunday. Similarly, the dosing intervals can include dosing every Monday and Thursday, but not on other days.

[0139] Administration of migalastat can be over a period of time. In one or more embodiments, migalastat is administered for a duration of at least 28 days, e.g., at least 30, 60, or 90 days, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, or 24 months, or at least 1, 2, or 3 years. In various embodiments, the migalastat therapy is long-term migalastat therapy for at least 6 months, e.g., at least 6, 7, 8, 9, 10, 11, 12, 16, 20, or 24 months, or at least 1, 2, or 3 years.

[0140] The administration of migalastat in accordance with the present invention may be in a formulation suitable for any route of administration, but is preferably administered in an oral dosage form such as a tablet, capsule, or solution. By way of example, a patient may be orally administered capsules containing 25 mg, 50 mg, 75 mg, 100 mg, or 150 mg of migalastat hydrochloride (i.e., 1-deoxygalactonojirimycin hydrochloride), or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt.

[0141] In some embodiments, the PC (e.g., migalastat or a salt thereof) is administered orally. In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered by injection. The PC may be accompanied by a pharmaceutically acceptable carrier, which may depend on the method of administration.

[0142] In one embodiment of the invention, the chaperone compound is administered as monotherapy and can be in a form suitable for any route of administration, including, for example, in tablet or capsule or liquid form for oral use, or in a sterile aqueous solution for injection. In another embodiment, the PC is provided as a dry, lyophilized powder that is added to the replacement enzyme formulation during or immediately after reconstitution to prevent enzyme aggregation in vitro prior to administration.

[0143] When the chaperone compound is formulated for oral administration, tablets or capsules may be prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form, for example, of solutions, syrups, or suspensions, or may be prepared as a dry product for constitution with water or another suitable vehicle before use. Such liquid formulations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). The formulations may also contain buffer salts, flavoring agents, coloring agents, and sweetening agents, as appropriate. Formulations for oral administration may be suitably formulated to give controlled release of the active chaperone compound.

[0144] Pharmaceutical formulations of chaperone compounds suitable for parenteral / injectable use generally include sterile aqueous solutions (where water soluble), or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, and the like. In many cases, it will be advisable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0145] Sterile injectable solutions are prepared by blending the required amount of purified enzyme and chaperone compound in an appropriate solvent with various other ingredients as enumerated above, as needed, followed by filtration or terminal sterilization. Generally, dispersions are prepared by blending the various sterilized active ingredients in a sterile vehicle containing the basic dispersion medium and the other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof.

[0146] The formulation may contain an excipient. Pharmaceutically acceptable excipients that may be included in the formulation include buffers, such as citrate buffer, phosphate buffer, acetate buffer, bicarbonate buffer, amino acids, urea, alcohols, ascorbic acid, and phospholipids; proteins such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA, and sodium chloride; liposomes; polyvinylpyrollidone; sugars such as dextran, mannitol, sorbitol, and glycerol; propylene glycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol; glycine or other amino acids; and lipids. Buffer systems used with the formulation include citrate, acetate, bicarbonate, and phosphate buffers. Phosphate buffers are a preferred embodiment.

[0147] The route of administration of the chaperone compound may be oral or parenteral, including intravenous, subcutaneous, intra-arterial, intraperitoneal, intraocular, intramuscular, buccal, rectal, intravaginal, intraorbital, intracerebral, intradermal, intracranial, intraspinal, intraventricular, intrathecal, intracisternal, intravesicular, intrapulmonary, intranasal, transmucosal, transdermal, or by inhalation.

[0148] Administration of the chaperone compound in the parenteral formulations described above may be by periodic injection of a bolus of the formulation, or by intravenous or intraperitoneal administration from an external (e.g., an IV bag) or internal (e.g., a bioerodible implant) reservoir.

[0149] The embodiments relating to pharmaceutical formulations and administration may be combined with any of the other embodiments of the invention, such as embodiments relating to methods of treating patients with Fabry disease, methods of enhancing alpha-galactosidase A in patients diagnosed with or suspected of having Fabry disease, embodiments relating to the use of a pharmacological chaperone for alpha-galactosidase A for the manufacture of a medicament for the treatment of patients diagnosed with Fabry disease, or embodiments relating to a pharmacological chaperone for alpha-galactosidase A for use in the treatment of patients diagnosed with Fabry disease, and embodiments relating to applicable mutations, PCs and suitable dosages thereof.

[0150] In one or more embodiments, the chaperone is administered in combination with enzyme replacement therapy. Enzyme replacement therapy increases the amount of protein by exogenously introducing a wild-type or biologically functional enzyme via infusion. As discussed above, this therapy has been developed for many genetic disorders, including lysosomal storage disorders such as Fabry disease. After injection, the exogenous enzyme is assumed to be taken up into tissues via nonspecific or receptor-specific mechanisms. Generally, uptake efficiency is not high, and the circulation time of exogenous proteins is short. In addition, exogenous proteins are unstable, subject to rapid intracellular degradation, and may cause adverse immune reactions with subsequent treatment. In one or more embodiments, the chaperone is administered simultaneously with the replacement enzyme. In some embodiments, the chaperone is formulated with the replacement enzyme.

[0151] In one or more embodiments, the patient is switched from enzyme replacement therapy (ERT) to migalastat therapy. In some embodiments, a patient receiving ERT is identified, the patient's ERT is discontinued, and the patient begins receiving migalastat therapy. The migalastat therapy can be according to any of the methods described herein. In various embodiments, the patient has some degree of renal dysfunction, such as mild, moderate, or severe renal dysfunction.

[0152] Monitoring Lyso-Gb3 and Migalastat levels Monitoring lyso-Gb3 (globotriaosylsphingosine) can determine whether the substrate is being cleared from the body of Fabry patients. High lyso-Gb3 levels correlate with high substrate levels. If the patient is successfully treated, lyso-Gb3 levels will likely decrease. One dosing regimen for Fabry disease involves administering about 100 mg to about 300 mg FBE of migalastat or its salts to the patient once every other day.

[0153] Over time, lyso-Gb3 levels may increase, which can be due to either disease progression and / or a decreased ability of the kidneys to clear migalastat from the patient's body. At high levels, migalastat acts as an inhibitor of α-Gal A, thus preventing the enzyme from binding to its target substrate; therefore, if migalastat levels are too high, Lyso-Gb3 levels will increase. Individuals with normal renal function will generally clear a 150 mg dose of migalastat hydrochloride by 48 hours (i.e., C 48h (Until the quantification level of approximately 5 ng / mL is reached). In severe renal impairment, C 48h can exceed 250 or even 300 ng / mL. Because migalastat has no other known interactions that could otherwise result in high levels, it is believed that the high migalastat levels are due to renal dysfunction.

[0154] Accordingly, another aspect of the present invention relates to methods for treating Fabry disease in patients with impaired renal function. In one or more embodiments, the method comprises administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a first frequency of once every other day for a first period of time; and administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at longer dosing intervals (e.g., once every 3 to 7 days) for a second period of time. In some embodiments, the dosing frequency is adjusted after measuring lyso-Gb3 and / or migalastat levels. In some embodiments, the dosing frequency is adjusted after a change in the patient's renal function (e.g., eGFR). For example, the dosing frequency may be adjusted in response to the patient's eGFR indicating a change from mild to moderate renal impairment or from moderate to severe renal impairment.

[0155] In some embodiments, migalastat or a salt thereof is administered at a first frequency for a first period of time, and then at a second frequency for a second period of time. The first frequency is greater than (i.e., more frequently than) the second frequency. The first and second frequencies can be any administration interval disclosed herein. In some embodiments, the first frequency is every other day, and the second frequency is every 3, 4, 5, 6, or 7 days. In some embodiments, the first frequency is every 4 days, and the second frequency is every 5, 6, or 7 days.

[0156] In some embodiments, migalastat or a salt thereof is administered at a first frequency for a first period of time, then at a second frequency for a second period of time, and then at a third frequency for a third period of time. The first frequency is greater than (i.e., more frequent than) the second frequency, which is greater than the third frequency. For example, in some embodiments, migalastat or a salt thereof is administered at a first frequency of once every other day for a first period of time, then migalastat or a salt thereof is administered at a second frequency of once every four days for a second period of time, and then migalastat or a salt thereof is administered at a third frequency of once every seven days for a third period of time.

[0157] In some embodiments, the administration frequency is adjusted in response to a decline in the patient's eGFR. In an exemplary embodiment, if the patient's eGFR is 30 mL / min / 1.73 m 2 When the patient's eGFR drops below 20 mL / min / 1.73 m, the dosing frequency can be adjusted from every other day to every four days. In an exemplary embodiment, 2 When the blood pressure drops below 1000 kcal, the dosing frequency can be adjusted from every 4 days to every 7 days. Other adjustments in dosing frequency may be made from one dosing interval as described above to a longer dosing interval. In some embodiments, the patient suffers from severe renal impairment.

[0158] In some embodiments, the method further comprises measuring migalastat levels. In one or more embodiments, the migalastat concentration (e.g., ng / mL) is measured. In some embodiments, the total area under the curve (AUC 0-∞ In one or more embodiments, the minimum concentration (C) of migalastat reached by the next dose is measured. trough ) is measured. trough is the concentration at 48 hours (C 48h ) would be Q4D C trough is the concentration at 96 hours (C 96 ) will be. Similarly, C of Q7D trough is the concentration at 168 hours (C 168 In one or more embodiments, the targeted C trough The value is below the lower limit of quantitation (BLQ) or close to it. trough The values ​​indicate that migalastat is cleared from the body at an adequate rate (ie, nearly completely cleared by the time the next dose is administered).

[0159] Migalastat levels can be measured using methods known in the art. For example, when measuring migalastat from tissue samples, a tissue aliquot can be homogenized (7 μL of water per mg of tissue) using a homogenizer (e.g., FastPrep-24 from MP Biomedical, Irvine, CA). 100 μL of tissue homogenate or 50 μL of plasma in a microcentrifuge tube can then be spiked with 500 ng / mL 13C d2-AT1001 HCl internal standard (MDS Pharma Services). 600 μL of 5 mM HCl in 95 / 5 MeOH:H2O can then be added, and the tubes can be vortexed for 2 minutes, followed by centrifugation at 21,000 × g for 10 minutes at room temperature. The supernatant can then be collected in a clean 96-well plate, diluted with 5 mM HCl in dH2O, and applied to a 96-well solid-phase extraction (SPE) plate (Waters Corp., Milford, MA). After several washing steps and elution into a clean 96-well plate, the extract can be dried under N2 and reconstituted with mobile phase A. Migalastat levels can then be determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) (e.g., LC: Shimadzu; MS / MS: ABSciex API 5500 MS / MS). Liquid chromatography can be performed on a Halo HILIC column (150 × 4.6 mm, 2.7 μm) (Advanced Materials Technology, Inc.) at a flow rate of 0.7 mL / min using a binary ACN:water:formate mobile phase system (Mobile Phase A: 95:5 ACN:5 mM ammonium formate in water, 0.5% formic acid; Mobile Phase B: 5:47.5:47.5 ACN:MeOH:5 mM ammonium formate in water, 0.5% formic acid). MS / MS analysis can be performed in APCi positive ion mode. The same procedure, except for homogenization, can be followed for the determination of migalastat in plasma. The following precursor ion → product ion transitions can be monitored: mass / charge (m / z) 164.1 → m / z 80.1 for migalastat and m / z 167.1 → m / z 83.1 for the internal standard. A 12-point calibration curve and quality control samples can be prepared.The ratio of the area under the curve for migalastat to the internal standard is then determined, and the final concentration of migalastat in each sample is calculated using a linear least-squares fit equation applied to the calibration curve. To derive approximate molar concentrations, 1 gram of tissue can be extrapolated to a volume of 1 mL.

[0160] By measuring the migalastat concentration in plasma samples taken at various times, clearance from the body can be monitored. trough A clinically relevant increase in C indicates a significant accumulation of plasma migalastat concentrations. If migalastat is not sufficiently cleared from the body before the next dose is administered, migalastat levels may then increase, potentially leading to inhibitory effects. Therefore, in one or more embodiments, a change in dosing frequency may be achieved in patients with normal renal function C. trough Compared to C trough In one or more embodiments, the C of normal renal function is measured after a 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0-fold increase in C of normal renal function. trough is the BLQ. In some embodiments, the BLQ is 5 ng / mL of migalastat. A person with normal renal function will generally clear 150 mg of migalastat HCl in 48 hours. Therefore, a patient currently on a QOD regimen of 150 mg of migalastat HCl should reach the BLQ by 48 hours, which is also the C trough If a patient on a QOD dosing regimen measures a value above the BLQ at 48 hours, this may indicate a need to modify the dosing interval. Thus, in one or more embodiments, the C value of patients with impaired renal function is trough value (C if on QOD regimen) 48h , C if on Q4D regimen 96 or C if on Q7D regimen 168 ) is C for people with normal renal function trough (C 48h ) will be compared with

[0161] In one or more embodiments, the change in dosing frequency is determined by the normal renal function AUC 0-∞ Compared with AUC 0-∞ This is performed after a 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 or 3.0-fold increase in the concentration of HCl.

[0162] In some embodiments, samples may be collected at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and / or 168 hours after administration. In some embodiments, the migalastat concentration is measured 48 hours after administration. In some embodiments, the second period of administration begins after measuring greater than about 5, 10, 15, 20, 25, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, or 200 ng / mL of migalastat 48 hours after administration of migalastat during the first period of administration.

[0163] In a further embodiment, the method further comprises measuring lyso-Gb3 in one or more plasma samples from the patient. A first baseline lyso-Gb3 level may be determined during the first period. As used herein, "baseline lyso-Gb3 level" refers to the lowest plasma lyso-Gb3 value measured during a given period or administration regimen. Thus, a significant increase in lyso-Gb3 level from the baseline lyso-Gb3 level may indicate progression of renal disease and / or inadequate clearance of migastat. Thus, in a further embodiment, a second period of administration is initiated after an increase (e.g., an increase of at least about 20, 25, 30, 33, 35, 40, 45, or 50% and / or 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, or 3 nM) above the first baseline lyso-Gb3 level is measured. Based on phase 3 data in Fabry patients suggesting inhibition-induced migalastat exposure due to either declining renal function and / or progression of the disease state, a 33% and / or 2 nM increase in plasma lyso-Gb3 from baseline is considered clinically relevant. Lyso-Gb3 levels may be measured at various frequencies (e.g., about once every 2, 3, 4, or 5 months). Once a dosing regimen is initiated, it is believed to take approximately 3 months for baseline lyso-Gb3 levels to be established.

[0164] Lyso-Gb3 can be measured by methods known in the art using validated assays. Similar to migalastat, lyso-Gb3 levels may be determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS) (e.g., LC: Shimadzu; MS / MS: ABSciex API 5500MS / MS). For example, one method for measuring plasma lyso-Gb3 is described in Hamler, Rick, et al., "Accurate quantitation of plasma globotriaosylsphingosine (lyso-Gb3) in normal individuals and Fabry disease patients by liquid chromatography-tandem mass spectrometry (LC-MS / MS)," Molecular Genetics and Metabolism, Volume 114.2 (2015): S51. In one or more embodiments, lyso-Gb3 is measured in a sample from the patient's urine.

[0165] Thus, in one exemplary embodiment, the method comprises: administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a first frequency of once every other day for a first period of time; administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a second frequency of once every 4 or 7 days for a second period of time; measuring lyso-Gb3 in one or more plasma samples from the patient; determining a first baseline lyso-Gb3 level during a first time period; Migalastat concentration in one or more plasma samples during the first period, AUC 0-∞ and / or C. trough measuring; and The second frequency of administration is (i) after a first increase above baseline lyso-Gb3 levels; and / or (ii) a migalastat level greater than about 5 ng / mL measured 48 hours after administration of migalastat during the first period, or an AUC 0-∞ and / or C. trough After a greater than 1.5-fold increase in To start Includes:

[0166] In further embodiments, the second period of administration can begin after an increase of at least about 30, or 33% over the first baseline lyso-Gb3 level and / or after greater than 2 nM and / or about 50 ng / mL of migalastat is measured 48 hours after administration of migalastat during the first period of administration. In some embodiments, the second period of administration begins after an increase of at least about 30, or 33% over the first baseline lyso-Gb3 level and / or after greater than 2 nM and / or about 50 ng / mL of migalastat is measured 48 hours after administration of migalastat during the first period of administration, or ... 0-∞ and / or C. trough may begin after a greater than 1.5-fold increase in

[0167] In a further embodiment, administration is adjusted from every other day to every four days, and then further adjusted to every seven days. In such an embodiment, the frequency for the second period is once every four days, and the method further comprises administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a third frequency of once every seven days for a third period. In yet another embodiment, the method comprises: measuring lyso-Gb3 in one or more plasma samples from the patient; determining a first baseline lyso-Gb3 level during a first time period; Migalastat concentration in one or more plasma samples from patients during the first period, AUC 0-∞ and / or C.trough To measure; The second period of administration comprises: (i) after a first increase above baseline lyso-Gb3 levels, and (ii) after a migalastat measurement of greater than about 5 ng / mL 48 hours after administration of migalastat during the first time period; or an AUC 0-∞ and / or C. trough After a greater than 1.5-fold increase in To start determining a second baseline lyso-Gb3 level during a second period; and The third period of administration is (i) after a second increase above baseline lyso-Gb3 levels, and (ii) A migalastat level greater than about 5 ng / mL measured 48 hours after administration of migalastat during the second period, or an AUC 0-∞ and / or C. trough After a greater than 1.5-fold increase in To start It may further include:

[0168] In other embodiments, dosing is adjusted directly from every other day to every seven days, rather than initially adjusting to every four days.

[0169] In an exemplary embodiment, a Fabry patient may receive 150 mg of migalastat HCl every other day. If, upon measurement of plasma lyso-Gb3 levels, the following is measured: (1) an increase in plasma lyso-Gb3 (e.g., at least a 30 or 33% increase) compared to baseline levels for the current dosing regimen; and / or (2) an increase in plasma lyso-Gb3 of at least 2 nM compared to baseline levels for the current dosing regimen, the dosing regimen may be changed to once every four or seven days. If the patient's migalastat levels are high, the regimen may also be changed to once every four or seven days. Such high migalastat levels are associated with a high AUC (e.g., a 1.5- or 2-fold increase) compared to normal renal function during the first period. 0-∞ and / or C. trough can be a measurement of

[0170] After changing the dose regimen, a new plasma lyso-Gb3 baseline level will be established. Any new dose regimen modification will be based on a comparison with the subject's most recent baseline level. For example, a new baseline level may be established as follows: if the subject exhibits a decrease in plasma lyso-Gb3 compared to their previous measurement, a confirmatory retest may be performed. If the confirmatory value is also lower than their previous measurement, the average of these two values ​​will become the subject's new baseline level. If the retest is not lower than the subject's previous measurement, the previous measurement will constitute the current baseline level until the next visit.

[0171] Throughout this specification, the phrases "one embodiment," "particular embodiment," "various embodiments," "one or more embodiments," or "an embodiment" mean that the particular feature, structure, material, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Thus, the appearance of phrases such as "in one or more embodiments," "particular embodiment," "various embodiments," "in one embodiment," or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0172] Although the invention herein has been described with reference to detailed embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made in the method and apparatus of the present invention without departing from the spirit and scope of the invention. Therefore, it is intended that the present invention cover such modifications and variations provided they come within the scope of the appended claims and their equivalents.

[0173] Patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entirety for all purposes. [Example]

[0174] Example 1: Pharmacokinetics of migalastat in non-Fabry patients with renal impairment A phase 1 study was conducted to investigate the pharmacokinetics and safety of migalastat HCl in non-Fabry subjects with impaired renal function. Results are reported in Johnson, et al., "An Open-Label Study to Determine the Pharmacokinetics and Safety of Migalastat HCl in Subjects With Impaired Renal Function and Healthy Subjects with Normal Renal Function," American College of Clinical Pharmacology 4.4 (2015):256-261, and are also described herein. Subjects with mild, moderate, and severe renal impairment and normal renal function received a single 150 mg dose of migalastat HCl. eGFR was estimated using the Cockcroft-Gault equation in accordance with FDA guidance for studies of renal impairment.

[0175] Volunteers were asked to measure creatinine clearance (CL CR The subjects were enrolled in two cohorts stratified by renal function calculated using the Cockcroft-Gault formula. CR For each subject, the following plasma migalastat PK parameters were determined by non-compartmental analysis with WinNonlin® software (Pharsight Corporation, version 5.2): C max Highest measured concentration t max Time to reach maximum concentration AUC 0-t Area under the concentration-time curve from time 0 to the last measurable concentration, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations AUC 0-∞Area under the concentration-time curve, extrapolated to infinity, calculated using the following formula: AUC0-∞=AUC0-t+Ct / λZ where Ct is the final measurable concentration and λZ is the apparent terminal elimination rate constant. λz apparent terminal elimination rate constant, where λz is the magnitude of the slope of the linear regression of the log concentration versus time profile in the terminal phase t 1 / 2 Apparent terminal elimination half-life (if available), where t 1 / 2 =(ln2) / λZ CL / F Oral clearance calculated as dose / AUC0-∞ Vd / F Oral volume of distribution calculated as dose / AUC0-∞·λZ C 48h 48-hour concentration after administration

[0176] The pharmacokinetic parameters to be determined were: AUC (Area under 0-t ) and extrapolated to infinity (AUC 0-∞ ) Area under the concentration-time curve (AUC), maximum observed concentration (C max ), C max Arrival time (t max ), 48-hour concentration after administration (C 48h ), terminal elimination half-life (t 1 / 2 ), oral clearance (CL / F), and apparent terminal elimination rate constant (λz) (ClinicalTrials.gov registration: NCT01730469).

[0177] Test subjects had creatinine clearance (CL) as determined using the Cockcroft-Gault formula. CR ) is less than 90 mL / min (i.e., CL CR Renal dysfunction was defined as occurring if the CLcr was <90 mL / min. Subjects were classified according to the degree of renal dysfunction: mild (CLcr ≥ 60 and <90 mL / min), moderate (CL CR ≥30 and <60 mL / min), or severe (CL CR ≥15 and <30 mL / min)

[0178] The plasma and urinary pharmacokinetics of migalastat have been investigated in healthy volunteers and Fabry patients with normal to mild renal impairment. In single-dose studies, migalastat had a moderate absorption rate, reaching peak concentrations approximately 3 hours (range, 1 to 6 hours) after oral administration across the entire dose range tested. Mean C max and AUC 0-t The values ​​increased dose-proportionally after oral doses of 75 mg to 1250 mg migalastat. The mean elimination half-life (t 1 / 2 The mean urinary recovery time (TQT) ranged from 3.04 to 4.79 hours. The mean percentage of dose recovered in urine from the doses evaluated in the single ascending dose (SAD) study was 32.2%, 43.0%, 49.3%, and 48.5% for the 25 mg, 75 mg, 225 mg, and 675 mg dose groups, respectively. Only minimal accumulation of plasma migalastat was observed in the multiple ascending dose study. In the total quality of life (TQT) study, migalastat had negative effects on cardiac repolarization at single doses of 150 mg and 1250 mg (Johnson et al. "Pharmacokinetics and Safety of Migalastat HCl and Effects on Agalsidase Activity in Healthy Volunteers." Clin Pharmacol Drug Dev. 2013 Apr;2(2):120-32).

[0179] In this single-dose renal impairment study conducted in non-Fabry subjects, plasma concentrations of a single 150 mg dose of migalastat HCl increased with increasing degrees of renal impairment compared with subjects with normal renal function. After a single oral dose of 150 mg of migalastat HCl, the mean plasma migalastat AUC 0-∞ was increased by 1.2-fold, 1.8-fold, and 4.5-fold in subjects with mild, moderate, or severe renal impairment, respectively, compared with healthy control subjects. 0-∞ The increase in values ​​was statistically significant in subjects with moderate or severe renal impairment, but not in subjects with mild renal impairment, compared with subjects with normal renal function after a single dose. maxwas slightly delayed in the severe group; C max Plasma migalastat C did not increase across groups after a single oral dose of 150 mg migalastat HCl in subjects with various degrees of renal impairment compared with healthy control subjects. 48h Levels were moderate (mainly Cr) compared to healthy control subjects. CL <50 mL / min) and in subjects with severe renal impairment. 1 / 2 increased with increasing degree of renal impairment (arithmetic mean [min, max]: 6.4 [3.66, 9.47], 7.7 [3.81, 13.8], 22.2 [6.74, 48.3], and 32.3 [24.6, 48.0] hours for subjects with normal renal function and mild, moderate, or severe renal impairment, respectively). Mean CL / F decreased with increasing degree of renal failure, ranging from 12.1 to 2.7 L / hr for mild to severe renal impairment (Johnson et al. 2014).

[0180] Migalastat clearance decreased with increasing renal impairment, with migalastat HCl plasma t 1 / 2 , AUC 0-∞ , and C 48h The incidence of adverse events was similar across all renal function groups.

[0181] After a single oral dose of 150 mg migalastat HCl, plasma exposure (AUC 0-t (expressed as CL) increased with increasing degree of renal dysfunction. CR As the value decreases, the AUC of migalastat 0-t Figure 1B shows the mean (SE) plasma migalastat concentration-time profiles for each renal function group. BLQ values ​​were entered as 0 and included in the calculation of the mean values.

[0182] As shown in Figure 1C, the plasma migalastat AUC 0-tThe results showed that, especially in subjects with severe renal impairment, the plasma clearance of migalastat decreased as renal impairment worsened, resulting in a decrease in t 1 / 2 becomes longer, and C 48h values ​​and overall plasma exposure (AUC 0-∞ ) was demonstrated. Migalastat is primarily excreted unchanged in the urine. Therefore, increased plasma migalastat exposure is consistent with worsening renal dysfunction.

[0183] Conclusion: Plasma migalastat clearance decreased with increasing degree of renal dysfunction.

[0184] A summary of the PK results is shown in Table 3 below.

[0185] [Table 53]

[0186] Example 2: Multiple Dose Simulation for Renally Impaired Subjects In the renal impairment study of Example 1, the area under the curve (AUC) and trough concentration of migalastat at 48 hours post-dose following a QOD dose were significantly higher in subjects with eGFR values ​​≦35 mL / min compared to subjects with normal renal function (C 48h ) was observed.

[0187] A population PK model was developed to predict exposure and time above IC50 in Fabry patients with varying degrees of renal impairment. 2 To better understand migalastat exposure in patients with rheumatoid arthritis, various dosing regimens were evaluated. The dosing regimens evaluated included 150 mg every other day (QOD), 150 mg every four days (Q4D), and 150 mg once weekly (Q7D).

[0188] A model-based dose-finding approach was used to predict the appropriate migalastat dose setting in a subpopulation of Fabry patients, i.e., Fabry patients with renal impairment. Generally, dose optimization goals to which model-based drug development (MBDD) methods can be applied include: (1) predicting the first-in-human dose; (2) finding the dose or dose range that best balances safety and efficacy; (3) finding the best dosing frequency; (4) finding promising combinations of co-administered drugs; (5) considering real-world subject behavior, including adherence; and (6) maximizing early knowledge to enhance dose confirmation.

[0189] This example provides a computer simulation of the administration of Example 1 to subjects with impaired renal function. A key assumption was that the exposure characterized for non-Fabry subjects with impaired renal function was the same as for Fabry patients with impaired renal function. The software program was WinNonlin, version 5.2 or higher. The model conditions are described below. The modeling exercise included BSA-adjusted eGFR コッククロフト·ゴールト ≦35mL / min / 1.73m 2 Eleven subjects were included; three had moderate renal impairment but not >30 mL / min / 1.73 m 2 and ≤35 mL / min / 1.73 m 2 and 8 patients had a blood pressure of ≥ 14 mL / min / 1.73 m 2 and <30 mL / min / 1.73 m 2 Steady state was assumed by the seventh dose.

[0190] Four regimens with 150 mg migalastat HCl were simulated: QOD (every other day or every 48 hours), Q3D (every 3 days or every 72 hours), Q4D (every 4 days or every 96 hours), and Q7D (every 7 days / week or every 168 hours).

[0191] From the single-dose data, a two-compartment model was used to calculate the volume of distribution (V d) and elimination rate constants were estimated. These estimates were input into each molecular dose simulation regimen.

[0192] Figures 2A-2D show the mean simulation plots for each regimen. Exposure and accumulation ratios are shown in Table 4 below. Based on AUC, MD simulations suggest minimal accumulation (<5%) for Q7D dosing. The highest migalastat exposure in Fabry patients was recorded as 53,035 ng×hr / mL, in patients receiving a single 450 mg dose.

[0193] Table 5 below shows the C of the 150 mg regimen. min,ss C min,ss Based on this, the MD simulations of Q7D are PPK C for most of the targets. min (8.70ng / mL).

[0194] Figures 3A and 3B show the R of all simulated regimens. ac and C min Figure 3A shows that in severe renal impairment, migalastat accumulation was greater with the QOD regimen, then less with Q3D, Q4D, and virtually none with Q7D. Figure 3B also shows that C 48h This tendency is observed regardless of concentration.

[0195] FIG. 4 shows the C from Example 1. 48h This stick plot shows the AUC versus C across all levels of renal function. 48h It provides a visual correlation of the concentration and demonstrates that there is a good visual correlation between these two values.

[0196] Below is an overview of population PK modeling and IC 50 Tables 6-7 showing the time to exceed (inhibition) are provided.

[0197] Based on predicted exposure data, clinical trial simulations suggest that the Q4D regimen is 30 mL / min / 1.73 m 2Higher 40mL / min / 1.73m 2 that the Q7D regimen would result in exposure similar to that in subjects with normal renal function who have a lower eGFR, and ... 2 Higher 30mL / min / 1.73m 2 This suggests that exposure would be similar to that in subjects with normal renal function who have a lower eGFR.

[0198] This modeling predicts slower elimination of migalastat based on the level of renal impairment and adjusts the dosing frequency to result in levels of migalastat below those that would inhibit enzyme activity.

[0199] eGFR 20 mL / min / 1.73 m 2 Simulated migalastat exposure after Q7D in subjects with <100 mg / kg / day remained 5- to 6-fold higher compared to subjects with normal renal function.

[0200] [Table 54]

[0201] [Table 55]

[0202] [Table 56]

[0203] [Table 57]

[0204] Example 3: Pharmacokinetics of migalastat in Fabry patients with renal impairment The above computer modeling provides a scenario of plasma migalastat exposure but does not consider renal impairment in Fabry patients. That is, the data do not include a pharmacodynamic component (plasma lyso-GB3). Therefore, two Fabry patients with renal impairment were evaluated. One patient (P1) had moderate renal impairment, and the other patient (P2) had severe renal impairment. Table 8 below shows the plasma migalastat concentrations of P1 compared with moderately impaired subjects from a Phase 3 study by Amicus Therapeutics, Inc. (the FACETS study, Clinical Trial NCT00925301) and the renal impairment study in Example 1. There were two sets of migalastat concentration measurements taken six months apart, and the patient had previously been treated with migalastat. Table 9 shows similar information for P2, but compared with the severely impaired patient from the renal impairment study in Example 1. The FACETS study was conducted in Fabry patients with applicable mutations, in which population PK was performed from sparse blood sampling. Comparison with the results of the FACETS study allowed for comparison of PK in the Fabry population, which included mostly normal, but some mildly and some moderately impaired Fabry patients. No patients with severe renal impairment were included in the study.

[0205] [Table 58]

[0206] [Table 59]

[0207] As can be seen in Table 8, C 48h Concentrations increased by 49% over 6 months but remained similar to non-Fabry subjects with moderate renal impairment in Example 1. max C increased by 33% over 6 months, but remains similar to Example 1. 24h The eGFR is the same as in Example 1 for moderate renal impairment. MDRDalso remained within the range of moderate impairment (32 mL / min).

[0208] The percentages in parentheses are the coefficients of variation, which are relatively high and correspond to the variability of the time 0 h or time 48 h concentrations. This result is likely due to half of the subjects from Example 1 with moderate renal impairment having low concentrations and half having high concentrations.

[0209] For P1, the concentration at 48 hours is higher than the concentration at time 0 (columns 3 and 4), but for the moderately impaired person from Example 1, the concentration at 48 hours is the same as at time 0. This is because for P1, separate blood samples were taken at time 0 and time 48. However, Example 1 used the repeat dose modeling simulation output from the single dose data, so the values ​​are identical.

[0210] A similar trend can be seen in Table 9. Thus, Tables 8 and 9 confirm similar migalastat pharmacokinetics in Fabry and non-Fabry patients with similar renal impairment.

[0211] FIG. 5 shows the plasma migalastat trough concentrations (C) of Fabry patients for the renal dysfunction study of Example 1. 48h ) is shown. Figure 6 shows the mean (SD) renal impairment study exposure versus estimated AUC in Fabry patients. As can be seen in this figure, P1 and P2 followed the general trend of renal impairment study results in non-Fabry patients.

[0212] Table 10 below shows Lyso-GB3 / eGFR for P1.

[0213] [Table 60]

[0214] 32mL / min / 1.73m 2Despite continued deterioration in renal function down to an eGFR of , plasma lyso-GB3 showed no clinically relevant changes from the previous visit, and plasma migalastat concentrations remained similar to those observed in non-Fabry patients with moderate renal impairment.

[0215] This study demonstrates that renal dysfunction and pharmacokinetic trends in Fabry patients correlate with those in non-Fabry patients, and therefore computer modeling can be relied upon to select an appropriate dosing regimen (i.e., every 2, 4, or 7 days).

[0216] Example 4: Additional Simulations for Renally Impaired Subjects This example provides an additional computer simulation of migalastat administration to subjects with renal impairment from Example 1.

[0217] 7A-7D show simulated median and measured migalastat concentrations over time in normal, severe, mild, and moderately impaired renal subjects, respectively. The data are presented in Table 11 below:

[0218] [Table 61]

[0219] 8A to 8D show the C max ,AUC,C min and C 48h Shows.

[0220] Figures 9A-9D show steady-state predictions for QOD. The dashed lines are the average values ​​from the QT study. Figures 10A-10D show the C, C, and C, respectively, for the same simulations. max ,AUC,C min and C 48h Shows.

[0221] 11A-11B compare migalastat concentrations after administration of 100 mg migalastat over 96 hours in patients with moderate renal impairment with administration of 150 mg migalastat over 48 hours in patients with normal renal function. FIGS. 12A-12D show the C, C, and C, respectively, for the same simulations. max ,AUC,C min and C 48h Compare.

[0222] Example 5: Proposed Study to Determine the Safety, Pharmacokinetics, and Pharmacodynamics of Migalastat HCl in Fabry Patients with Applicable Mutations and Severe Renal Impairment Applicable mutations and severe renal dysfunction (i.e., eGFR 30 mL / min / 1.73 m 2 A study is proposed to determine the safety, pharmacokinetics, and pharmacodynamics of migalastat HCl in Fabry subjects with eGFR < 150 mg. Rather than lowering the dosage (i.e., to < 150 mg), the dose of 150 mg migalastat HCl was maintained but administered less frequently. MDRD Subjects with an eGFR of 10 or greater but less than 20 will receive this dose every 7 days (Q7D). MDRD Subjects with a renal function of 20 or greater but less than 30 will receive this dose every four days (Q4D). Subjects receiving the Q4D dose must have a renal function of 20 mL / min / 1.73 m 2 If the blood glucose level declines below Q7D, the subject will be changed to Q7D dosing regimen. Any subject who begins dialysis treatment or undergoes a kidney transplant will be discontinued from the study.

[0223] All subjects entering the study will be screened (Visit 1) to confirm eligibility for enrollment. Subjects who meet the eligibility criteria will attend a baseline visit (Visit 2) within 30 days of screening, including PK assessment. Visits will be scheduled every 3 months for a total of 12 months during the study. Based on the PK / PD results at each site visit, a follow-up visit or phone call will be scheduled one month later, as needed. If the PK / PD results indicate a need for a change in dosing regimen, subjects will be advised to adjust the time between doses and will undergo clinical laboratory evaluation either at each site or on-site.

[0224] Safety analysis Safety data will be monitored continuously, and specific discontinuation criteria will be developed for subjects who show evidence of decline in renal function: eGFR 10 mL / min / 1.73 m on two consecutive visits; 2 Subjects who achieve less than this will be required to discontinue migalastat and withdraw from the study.

[0225] Pharmacokinetic sampling Depending on each subject's starting migalastat regimen, complete PK blood collection will occur at Visit 2. Subjects starting on the Q4D regimen will have PK assessments performed pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24, 48, and 96 hours post-dose. Subjects starting on the Q7D regimen will have PK assessments performed pre-dose and at 1, 2, 3, 4, 6, 8, 12, 24, 48, 96, and 168 hours post-dose. At subsequent visits, subjects will undergo sparse sampling at 24, 48, and 96 hours post-dose for subjects on the Q4D regimen and at 24, 48, 96, and 168 hours for subjects on the Q7D regimen.

[0226] At Visit 2, subjects on the Q4D regimen will undergo a spot urine collection within 1 hour predose, followed by postdose whole urine collections during each dosing interval at 0-4, 4-8, 8-12, 12-24, 24-48, 48-72, and 72-96 hours. Urine collection intervals will be the same as for subjects on the Q7D regimen, with the addition of urine collections at 96-120, 120-144, and 144-168 hours for Q7D.

[0227] For subjects with a change in dose regimen, a complete PK blood and urine draw as detailed above will be performed at the visit following the regimen change.

[0228] Dosage regimen modifications This protocol allows for subject-specific dose regimen modifications. The starting dose for each subject may be 150 mg of migalastat HCl for an eGFR-based regimen, as described above. For subjects who begin the study on a Q4D regimen, eGFR must be ≥ 20 mL / min / 1.73 m on two consecutive visits (including follow-up visits). 2 A drop below this level would automatically result in a switch to the Q7D regimen.

[0229] At each visit, plasma lyso-Gb3 will be monitored. If the subject exhibits an increase in plasma lyso-Gb3 compared to their previous measurement, a confirmatory retest will be performed. If the confirmatory value is also higher than their previous measurement, the average of the two values ​​will become the subject's new baseline value. If the retest is not higher than the subject's previous measurement, there will be no new baseline value at that visit.

[0230] Stopping criteria will be applied on a subject-by-subject basis throughout the study. MDRD is 10mL / min / 1.73m 2 Subjects under 18 years of age or undergoing dialysis or kidney transplant will discontinue treatment. Subjects may also discontinue treatment at the discretion of the investigator and medical monitor.

[0231] Duration of study treatment After a screening period of up to 30 days, enrolled subjects will receive migalastat treatment for 12 months, at the end of which they may be eligible to enroll in a separate open-label extension study.

[0232] Judgment criteria Safety: Safety parameters include physical examination, vital signs (blood pressure, heart rate, respiratory rate, and temperature), 12-lead electrocardiogram, clinical laboratory parameters (serum chemistry, hematology, and urinalysis), eGFR, and adverse events.

[0233] PK: When available, the following PK parameters will be calculated based on plasma migalastat concentrations: maximum observed concentration (C max ), and the concentration at the end of the dosing interval at steady state (C trough ), mean plasma migalastat concentration over the dosing interval (C avg ), the time to reach the maximum concentration (t max ), apparent terminal elimination half-life (t 1 / 2 ), the area under the concentration-time curve from time 0 to the last measurable concentration (AUC 0-t ) and extrapolation to infinity (AUC 0-∞ ), and plasma clearance (CL / F).

[0234] Based on the urinary migalastat concentrations, the following PK parameters will be calculated: total amount excreted over the dosing interval (Ae 0-t ), the percentage of the dose recovered in the urine over the dosing interval (Fe), and renal clearance (CLr).

[0235] PD: PD parameters included plasma lyso-Gb3 and eGFR MDRD , and eGFR CKD-EPI Includes:

[0236] statistical methods Plasma migalastat concentrations will be determined by noncompartmental analysis from the PK blood and urine sample series using Phoenix®-WinNonlin® software, version 7.0 or later. Plasma migalastat sparse PK blood samples will be analyzed by a population PK model. The population PK model will evaluate and validate severe renal impairment dose regimen simulations and will be provided as separate reports. PK / PD modeling may also be investigated.

[0237] Continuous PD and safety data will be summarized using descriptive statistics (number, mean, median, minimum, and maximum). Categorical variables will be expressed by number (%).

[0238] Example 6: Pharmacokinetics of migalastat HCl in Fabry patients with severe renal impairment One patient (P3) enrolled in a previous migalastat study developed severe renal dysfunction (i.e., 30 mL / min / 1.73 m) in May 2016. 2 Treatment was discontinued as a result of an eGFR of less than 0.05. P3 received migalastat HCl Q4D starting in May 2017. PK data were collected every 3 months. Table 12 shows the PK data for P3 compared to patients receiving QOD with various levels of renal function.

[0239] [Table 62]

[0240] Table 13 shows the plasma migalastat concentrations of P3 after administration at various time points.

[0241] [Table 63]

[0242] Table 14 shows Lyso-Gb3 and eGFR for P3 over time.

[0243] [Table 64]

[0244] FIG. 15 shows Lyso-Gb3 and eGFR in P3 over time.

[0245] The patents and scientific literature referred to herein establish knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, articles and scientific literature cited herein are hereby incorporated by reference.

[0246] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, workers skilled in the art will understand that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. 1. A method for treating Fabry disease in a patient with impaired renal function, comprising administering to said patient about 100 mg to about 300 mg free base equivalent (FBE) of migalastat or a salt thereof once every four days.

2. 10. The method of claim 1, wherein the patient has moderate renal impairment.

3. 10. The method of claim 1, wherein the patient has severe renal impairment.

4. The method of any one of claims 1 to 3, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A.

5. The method of any one of claims 1 to 4, wherein the migalastat is in a solid dosage form.

6. 6. The method of any one of claims 1 to 5, wherein the patient is administered about 123 mg FBE.

7. 6. The method of any one of claims 1 to 5, wherein the patient is administered about 150 mg of migalastat HCl.

8. The method of any one of claims 1 to 7, wherein the migalastat is administered orally.

9. 1. A method for treating Fabry disease in a patient with impaired renal function, comprising administering to said patient about 100 mg to about 300 mg free base equivalent (FBE) of migalastat or a salt thereof once every seven days.

10. 10. The method of claim 9, wherein the patient has moderate renal impairment.

11. 10. The method of claim 9, wherein the patient has severe renal impairment.

12. The method of any one of claims 9 to 11, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A.

13. The method of any one of claims 9 to 12, wherein the migalastat is in a solid dosage form.

14. 14. The method of any one of claims 9 to 13, wherein the patient is administered about 123 mg FBE.

15. 14. The method of any one of claims 9 to 13, wherein the patient is administered about 150 mg of migalastat HCl.

16. The method of any one of claims 9 to 15, wherein the migalastat is administered orally.

17. 1. A method of treating Fabry disease in a patient with impaired renal function, comprising: administering to the patient about 100 mg to about 300 mg free base equivalent (FBE) of migalastat or a salt thereof at a first frequency once every other day for a first period of time; and administering to said patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a second frequency of less than once every other day for a second period of time. A method comprising:

18. 18. The method of claim 17, wherein the second frequency ranges from once every three days to once every seven days.

19. 19. The method of claim 17 or 18, wherein the second frequency is once every four days or once every seven days.

20. 20. The method of any one of claims 17-19, wherein administration at the second frequency begins after a decline in the patient's estimated glomerular filtration rate (eGFR).

21. measuring lyso-Gb3 in one or more plasma samples from said patient; determining a first baseline lyso-Gb3 level during said first period; the migalastat concentration, AUC, in one or more plasma samples from said patient during said first period; ０－∞ and / or C ｔｒｏｕｇｈ measuring; and administering at the second frequency (i) after said first increase above baseline lyso-Gb3 level; and (ii) after the first period of time is measured, a migalastat level of greater than about 5 ng / mL is measured 48 hours after administration of the migalastat, or after an AUC ０－∞ and / or C ｔｒｏｕｇｈ After a greater than 1.5-fold increase in To start The method of any one of claims 17 to 19, further comprising:

22. 22. The method of claim 21, wherein the increase over the first baseline lyso-Gb3 level is at least about 30% and / or 2 nM.

23. 23. The method of claim 21 or 22, wherein measuring migalastat comprises measuring a migalastat concentration, and wherein administration at the second frequency begins after greater than about 10 ng / mL of migalastat is measured 48 hours after administration of the migalastat during the first period of time.

24. Measuring migalastat is ０－∞ or C ｔｒｏｕｇｈ and measuring AUC compared to normal renal function. ０－∞ and / or C ｔｒｏｕｇｈ 23. The method of claim 21 or 22, wherein administration at the second frequency begins after a greater than two-fold increase in

25. 20. The method of any one of claims 17-19, wherein the second frequency is once every four days, and the method further comprises administering to the patient about 100 mg to about 300 mg FBE of migalastat or a salt thereof at a third frequency of once every seven days for a third period of time.

26. measuring lyso-Gb3 in one or more plasma samples from said patient; determining a first baseline lyso-Gb3 level during a first time period; the migalastat concentration, AUC, in one or more plasma samples from said patient during said first period; ０－∞ and / or C ｔｒｏｕｇｈ measuring; administering at the second frequency (i) after said first increase above baseline lyso-Gb3 level; and (ii) after a migalastat of greater than about 5 ng / mL is measured 96 hours after administration of said migalastat during said first period of time, or after an AUC of greater than about 5 ng / mL is measured during said first period of time compared to normal renal function ０－∞ and / or C ｔｒｏｕｇｈ After a greater than 1.5-fold increase in To start at; determining a second baseline lyso-Gb3 level during said second time period; and administering at the third frequency (i) after an increase above said second baseline lyso-Gb3 level; and (ii) after a migalastat of greater than about 5 ng / mL is measured 48 hours after administration of said migalastat during said second period, or after an AUC of greater than about 5 ng / mL is measured during said second period compared to normal renal function ０－∞ and / or C ｔｒｏｕｇｈ After a greater than 1.5-fold increase in To start 26. The method of claim 25, further comprising:

27. 27. The method of claim 26, wherein the increase over the first baseline lyso-Gb3 level is at least about 30% and / or 2 nM.

28. 28. The method of claim 26 or 27, wherein greater than about 10 ng / mL of migalastat is measured 48 hours after administration of the migalastat during the first period.

29. 20. The method of any one of claims 17 to 19, wherein the second frequency is once every 7 days.

30. measuring lyso-Gb3 in one or more plasma samples from said patient; determining a first baseline lyso-Gb3 level during said first period; the migalastat concentration, AUC, in one or more plasma samples from said patient during said first period; ０－∞ and / or C ｔｒｏｕｇｈ measuring; and administering at the second frequency (i) after said first increase above baseline lyso-Gb3 level; and (ii) after the first period of time is measured, a migalastat level of greater than about 5 ng / mL is measured 48 hours after administration of the migalastat, or after an AUC ０－∞ and / or C ｔｒｏｕｇｈ After a greater than 1.5-fold increase in To start 30. The method of claim 29, further comprising:

31. 31. The method of claim 30, wherein the increase over the first baseline lyso-Gb3 level is at least about 30% and / or 2 nM.

32. 32. The method of claim 30 or 31, wherein greater than about 10 ng / mL of migalastat is measured 48 hours after administration of the migalastat during the first period.

33. The method of any one of claims 17 to 32, wherein the patient has moderate renal impairment.

34. The method of any one of claims 17 to 32, wherein the patient has severe renal impairment.

35. 35. The method of any one of claims 17 to 34, wherein the migalastat is in a solid dosage form.

36. 36. The method of any one of claims 17-35, wherein the patient is administered about 123 mg FBE.

37. 36. The method of any one of claims 17-35, wherein the patient is administered about 150 mg migalastat HCl.

38. 38. The method of any one of claims 17 to 37, wherein the migalastat is administered orally.

39. The method of any one of claims 17 to 38, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A.

40. 1. Use of migalastat in the treatment of Fabry disease in a patient with impaired renal function, wherein the migalastat is administered less frequently than once every other day to a patient with Fabry disease and impaired renal function in an amount of about 100 mg to about 300 mg free base equivalent (FBE) of migalastat or a salt thereof.

41. 41. The use of claim 40, wherein the frequency ranges from once every three days to once every seven days.

42. 42. The use according to claim 40 or 41, wherein the frequency is once every four days.

43. 42. The use according to claim 40 or 41, wherein the frequency is once every 7 days.

44. The use according to any one of claims 40 to 43, wherein the patient has moderate renal impairment.

45. The use according to any one of claims 40 to 43, wherein the patient has severe renal impairment.

46. The use according to any one of claims 40 to 45, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A.

47. The use according to any one of claims 40 to 46, wherein the migalastat is in a solid dosage form.

48. 48. The use of any one of claims 40 to 47, wherein the patient is administered about 123 mg FBE.

49. 48. The use of any one of claims 40 to 47, wherein the patient is administered about 150 mg of migalastat HCl.

50. 50. The use according to any one of claims 40 to 49, wherein the migalastat is administered orally.

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