Methods for strengthening and / or stabilizing cardiac function in patients with Fabry disease

Abstract

Methods for treating Fabry disease in patients are provided. Certain methods relate to treating ERT-experienced or ERT-naive patients with Fabry disease. Certain methods involve administering to the patient about 100 mg to about 150 mg of the free base equivalent of migalastat to enhance and / or stabilize cardiac function. [Selected Figure] Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 550,984, filed August 28, 2017, which is incorporated herein by reference in its entirety.

[0002] Principles and embodiments of the present invention generally relate to the use of pharmacological chaperones for the treatment of lysosomal storage disorders, and in particular the use of migalastat for the treatment of Fabry disease. [Background technology]

[0003] Fabry disease is a progressive, X-linked inborn error of glycosphingolipid metabolism caused by mutations in the α-Gal A gene (GLA), resulting in a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A). Despite being an X-linked disorder, the degree of clinical manifestation that can occur in females varies widely. Fabry disease is rare, with an estimated incidence ranging from 1 in 40,000 to 1 in 117,000 males in the general population. Furthermore, there are variants of the late-onset phenotype of Fabry disease that do not exhibit classic signs and symptoms, potentially leading to underdiagnosis. Given these factors and newborn screening for Fabry disease, the actual incidence of Fabry disease may exceed current estimates.

[0004] Untreated, patients with Fabry disease have a shortened life expectancy, commonly resulting in death between the ages of 40 and 50. This disease is caused by vascular disease affecting the kidneys, heart, and / or central nervous system. Enzyme deficiency leads to intracellular accumulation of the substrate globotriaosylceramide (GL-3) in vascular endothelium and visceral tissues throughout the body. Progressive deterioration of renal function and azotemia, resulting from glycosphingolipid deposition, typically occur in the second to fourth decades of life but can occur as early as the teenage years. Renal involvement is observed in both hemizygous (male) and heterozygous (female) patients.

[0005] Cardiac disease as a result of Fabry disease affects most men and many women. Early cardiac findings include left ventricular enlargement, valvular disease, and conduction abnormalities. Mitral regurgitation is the most frequent valvular lesion typically presenting in childhood or adolescence. Cerebrovascular symptoms are primarily due to multiple small vessel lesions and may include thrombosis, transient ischemic attacks, basilar artery ischemia and aneurysms, stroke, hemiplegia, hemianesthesia, aphasia, labyrinthine disturbances, or cerebral hemorrhage. The average age at onset of cerebrovascular symptoms is 33.8 years. Personality changes and psychotic behavior may also become apparent with age.

[0006] One approved therapy for the treatment of Fabry disease is enzyme replacement therapy (ERT), which typically involves intravenous infusion of the corresponding wild-type protein in purified form. Currently, two α-Gal A products are available for the treatment of Fabry disease: agalsidase α (Replagal®, Shire Human Genetic Therapies) and agalsidase β (Fabrazyme®; Sanofi Genzyme Corporation). While ERT is effective in many settings, the treatment also has limitations. ERT has not been proven to reduce the risk of stroke, the myocardial response is slow, and GL-3 removal from some cell types in the kidney is limited. Some patients also develop an immune response to ERT.

[0007] Thus, there remains a need for therapies aimed at treating Fabry disease, and in particular for therapies aimed at enhancing cardiac function. Summary of the Invention

[0008] Various aspects of the present invention relate to the treatment of Fabry disease in ERT-naive and ERT-experienced patients with migalastat. Such treatment may include enhancing and / or stabilizing cardiac function, for example, enhancing and / or stabilizing midwall left ventricular fractional shortening (MWFS).

[0009] One aspect of the present invention relates to a method for enhancing cardiac function in a patient with Fabry disease, comprising administering to the patient every other day a formulation containing an effective amount of migalastat or a salt thereof, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE), for the purpose of enhancing cardiac function in the patient.

[0010] In one or more embodiments, enhancing cardiac function includes enhancing left ventricular systolic function.

[0011] In one or more embodiments, the patient has MWFS disorder prior to initiating administration of migalastat or a salt thereof. do .

[0012] In one or more embodiments, the patient has left ventricular hypertrophy (LVH) prior to initiation of administration of migalastat or a salt thereof. do .

[0013] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0014] In one or more embodiments, the patient is administered about 123 mg FBE of migalastat or a salt thereof every other day.

[0015] In one or more embodiments, the patient is administered about 123 mg of migalastat free base every other day.

[0016] In one or more embodiments, the patient is administered about 150 mg of migalastat hydrochloride every other day.

[0017] In one or more embodiments, the formulation includes an oral dosage form. In one or more embodiments, the oral dosage form includes a tablet, capsule, or liquid.

[0018] In one or more embodiments, migalastat or a salt thereof is administered for at least 12 months.

[0019] In one or more embodiments, the migalastat or a salt thereof is administered for at least 24 months.

[0020] In one or more embodiments, the patient is ERT naive.

[0021] In one or more embodiments, administration of migalastat or a salt thereof results in a mean increase in MWFS of at least about 1% in an ERT-naive patient population with MWFS disorders after migalastat or a salt thereof has been administered for 24 months.

[0022] In one or more embodiments, the patient is an ERT-experienced patient.

[0023] Another aspect of the present invention relates to a method for increasing MWFS in a patient with Fabry disease, the method comprising administering to the patient every other day a formulation comprising an effective amount of migalastat or a salt thereof, wherein the effective amount is about 100 mg to about 150 mg FBE, for the purpose of increasing the patient's MWFS.

[0024] In one or more embodiments, the patient has MWFS disorder prior to initiating administration of migalastat or a salt thereof. do .

[0025] In one or more embodiments, the patient has LVH prior to initiating administration of migalastat or a salt thereof. do .

[0026] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0027] In one or more embodiments, the patient is administered about 123 mg FBE of migalastat or a salt thereof every other day.

[0028] In one or more embodiments, the patient is administered about 123 mg of migalastat free base every other day.

[0029] In one or more embodiments, the patient is administered about 150 mg of migalastat hydrochloride every other day.

[0030] In one or more embodiments, the formulation includes an oral dosage form. In one or more embodiments, the oral dosage form includes a tablet, capsule, or liquid.

[0031] In one or more embodiments, migalastat or a salt thereof is administered for at least 12 months.

[0032] In one or more embodiments, the migalastat or a salt thereof is administered for at least 24 months.

[0033] In one or more embodiments, the patient is ERT naive.

[0034] In one or more embodiments, administration of migalastat or a salt thereof results in a mean increase in MWFS of at least about 1% in an ERT-naive patient population with MWFS disorders after migalastat or a salt thereof has been administered for 24 months.

[0035] In one or more embodiments, the patient is an ERT-experienced patient.

[0036] Another aspect of the present invention relates to a method for normalizing MWFS in a patient with Fabry disease and MWFS disorder, the method comprising administering to the patient every other day a formulation containing an effective amount of migalastat or a salt thereof, wherein the effective amount is about 100 mg to about 150 mg FBE, for the purpose of normalizing the patient's MWFS.

[0037] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0038] In one or more embodiments, the patient is administered about 123 mg FBE of migalastat or a salt thereof every other day.

[0039] In one or more embodiments, the patient is administered about 123 mg of migalastat free base every other day.

[0040] In one or more embodiments, the patient is administered about 150 mg of migalastat hydrochloride every other day.

[0041] In one or more embodiments, the formulation includes an oral dosage form. In one or more embodiments, the oral dosage form includes a tablet, capsule, or liquid.

[0042] In one or more embodiments, migalastat or a salt thereof is administered for at least 12 months.

[0043] In one or more embodiments, the migalastat or a salt thereof is administered for at least 24 months.

[0044] In one or more embodiments, the patient is ERT naive.

[0045] In one or more embodiments, administration of migalastat or a salt thereof results in a mean increase in MWFS of at least about 1% in an ERT-naive patient population with MWFS disorders after migalastat or a salt thereof has been administered for 24 months.

[0046] Another aspect of the present invention relates to a method for stabilizing MWFS in a patient with Fabry disease, the method comprising administering to the patient every other day a formulation comprising an effective amount of migalastat or a salt thereof, wherein the effective amount is about 100 mg to about 150 mg FBE, for the purpose of stabilizing the patient's MWFS.

[0047] In one or more embodiments, the patient has MWFS disorder prior to initiating administration of migalastat or a salt thereof. do .

[0048] In one or more embodiments, the patient has LVH prior to initiating administration of migalastat or a salt thereof. do .

[0049] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0050] In one or more embodiments, the patient is administered about 123 mg FBE of migalastat or a salt thereof every other day.

[0051] In one or more embodiments, the patient is administered about 123 mg of migalastat free base every other day.

[0052] In one or more embodiments, the patient is administered about 150 mg of migalastat hydrochloride every other day.

[0053] In one or more embodiments, the formulation includes an oral dosage form. In one or more embodiments, the oral dosage form includes a tablet, capsule, or liquid.

[0054] In one or more embodiments, migalastat or a salt thereof is administered for at least 12 months.

[0055] In one or more embodiments, the migalastat or a salt thereof is administered for at least 30 months.

[0056] In one or more embodiments, the patient is an ERT-experienced patient.

[0057] In one or more embodiments, administration of migalastat or a salt thereof results in a mean change in MWFS of greater than about -0.5% in an ERT-naive patient population with MWFS disorders after 30 months of administration of migalastat or a salt thereof.

[0058] Further features of the present invention will become apparent from the following description and accompanying drawings. [Brief explanation of the drawings]

[0059] [Figure 1A] 1A-1E show the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1). [Figure 1B] 1A-1E show the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1). [Figure 1C] 1A-1E show the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1). [Figure 1D] 1A-1E show the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1). [Figure 1E] 1A-1E show the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1). [Figure 2] The wild-type α-Gal A protein (SEQ ID NO: 2) is shown. [Figure 3] 1 shows the nucleic acid sequence encoding the wild-type α-Gal A protein (SEQ ID NO: 3). DETAILED DESCRIPTION OF THE INVENTION

[0060] 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 process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0061] Various aspects of the present invention relate to dosing regimens for administering pharmacological chaperones, such as migalastat, for the treatment of Fabry disease. In one or more embodiments, the migalastat dosing regimen enhances one or more cardiac parameters in a patient.

[0062] definition The terms used herein generally have their ordinary meanings in the art, within the context of this invention and within the specific context in which each term is used. Certain terms are explained below and elsewhere in this specification to provide additional guidance to the practitioner in describing the compositions and methods of the invention, and how to make and use them.

[0063] The term "Fabry disease" refers to an X-linked inborn error of glycosphingolipid catabolism resulting from deficient lysosomal α-Gal A activity. This defect leads to the accumulation of the substrate globotriaosylceramide (also known as "GL-3," Gb3, or ceramide trihexoside) and related glycosphingolipids in vascular endothelial lysosomes in the heart, kidney, skin, and other tissues. Another substrate for this enzyme is plasma globotriaosylsphingosine ("plasma lysoGb3").

[0064] The term "atypical Fabry disease" refers to patients who present with the primary cardiac manifestation of α-Gal A deficiency (i.e., progressive GL-3 accumulation in cardiomyocytes) leading to significant hypertrophy of the heart, particularly the left ventricle.

[0065] A "carrier" is a female who has one X chromosome with a defective α-Gal A gene and one X chromosome containing the normal gene, and in which X chromosome inactivation of the normal allele is present in one or more cell types. Carriers are often also diagnosed as having Fabry disease.

[0066] "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.

[0067] A "Fabry disease patient" refers to an individual who has been diagnosed with or is suspected of having Fabry disease and who has a mutant α-Gal A as further defined below. The characteristic markers of Fabry disease are expected to occur with equal prevalence in male hemizygotes and female carriers, although the disease is typically less severe in females.

[0068] 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 at GenBank Accession No. X14448.1 and is depicted in Figures 1A-1E (SEQ ID NO: 1). The human α-Gal A enzyme consists of 429 amino acids and is available at GenBank Accession Nos. X14448.1 and U78027.1 and is depicted in Figure 2 (SEQ ID NO: 2). The nucleic acid sequence containing only the coding region (i.e., exons) of SEQ ID NO: 1 is depicted in Figure 3 (SEQ ID NO: 3).

[0069] The term "mutant protein" encompasses proteins that have a mutation in the gene encoding the protein and, as a result, are unable to achieve a stable conformation under conditions under which the protein normally resides in the endoplasmic reticulum (ER). If a stable conformation cannot be achieved, a substantial amount of the enzyme is degraded and is not transported to the lysosome. Such mutations are sometimes referred to as "conformational mutants." Such mutations include, but are not limited to, missense mutations, small in-frame deletions, and insertions.

[0070] In one embodiment, the term "mutant α-Gal A" as used herein includes α-Gal A that has a mutation in the gene encoding α-Gal A, such that the enzyme is unable to achieve a stable conformation under conditions normally present in the ER. Inability to achieve a stable conformation results in substantial amounts of the enzyme being degraded and not being transported to lysosomes.

[0071] As used herein, the term "pharmacological chaperone" ("PC") refers to any molecule, such as a small molecule, protein, peptide, nucleic acid, carbohydrate, 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 location, preferably its native cellular location, i.e., preventing ER-associated degradation of the protein; (iii) preventing aggregation of misfolded proteins; and / or (iv) restoring or enhancing at least partial wild-type function and / or activity of the protein. A compound that specifically binds, such as α-Gal A, means that it binds to and exerts a chaperone effect on the enzyme, but not on a group of related or unrelated enzymes. More specifically, this term does not refer to endogenous chaperones, such as BiP, or nonspecific agents, such as glycerol and DMSO (deuterated water), i.e., chemical chaperones, that have demonstrated nonspecific chaperone activity for a variety of proteins. In one or more embodiments of the present invention, the PC may be a reversible competitive inhibitor. In one embodiment, the PC is migalastat or a salt thereof. In another embodiment, the PC is migalastat free base (e.g., 123 mg of migalastat free base). In yet another embodiment, the PC is a salt of migalastat (e.g., 150 mg of migalastat HCl).

[0072] A "competitive inhibitor" of an enzyme is a compound that is structurally similar to the chemical and molecular structure of the enzyme's substrate and binds to the enzyme at approximately the same site as the substrate. Thus, the inhibitor competes with the substrate molecules for the same active site, thereby increasing the Km. Competitive inhibitors are typically reversible if enough substrate molecules are available to displace the inhibitor. That is, competitive inhibitors allow for reversible binding. Therefore, the amount of enzyme inhibition is affected by the inhibitor concentration, the substrate concentration, and the relative affinities of the substrate and inhibitor for the active site.

[0073] 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 of 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 the protein, rather than a group of related or unrelated proteins. The amino acid residues of a protein that interact with a given pharmacological chaperone may or may not be within the "active site" of the protein. Specific binding may be assessed by routine binding assays or by structural studies (e.g., cocrystallization, NMR, and the like). The active site of α-Gal A is the substrate-binding site.

[0074] "Defective α-Gal A activity" refers to α-Gal A activity in cells from a patient that is below the normal range (using the same method) compared to the activity in a normal individual who does not have or is not suspected of having Fabry disease or any other disease (especially a blood disorder).

[0075] As used herein, the terms "enhancing α-Gal A activity" or "enhancing α-Gal A activity" refer to increasing the amount of α-Gal A adopting a stable conformation in cells contacted with an α-Gal A-specific pharmacological chaperone relative to the amount in cells (preferably, e.g., the same cell type or the same cells at an earlier stage) that have not been contacted with the α-Gal A-specific pharmacological chaperone. The terms also refer to increasing the trafficking of α-Gal A to lysosomes in cells contacted with an α-Gal A-specific pharmacological chaperone relative to the trafficking of α-Gal A not contacted with a protein-specific pharmacological chaperone. These terms refer to both wild-type and mutant α-Gal A. In one embodiment, the increase in intracellular α-Gal A levels is measured by measuring the hydrolysis of an artificial substrate in lysates from cells treated with PC. Increased hydrolysis indicates enhanced α-Gal A activity.

[0076] 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.

[0077] "Responders" refer to individuals diagnosed with or suspected of having a lysosomal storage disease (LSD), such as Fabry disease, who, in response to exposure to PC, have cells that exhibit sufficient enhanced α-Gal A activity and / or symptomatic remission or enhanced surrogate markers, respectively. Non-limiting examples of enhanced surrogate markers for Fabry disease are disclosed in LysoGB3 and U.S. Patent Application Publication No. 2010 / 0113517, which are incorporated herein by reference in their entirety.

[0078] Non-limiting examples of improvements in surrogate markers of Fabry disease disclosed in U.S. Patent Application Publication No. 2010 / 0113517 include increased α-Gal A levels or activity in cells (e.g., fibroblasts) and tissues; 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 lyso-Gb3; decreased cardiac (especially left ventricular) hypertrophy, amelioration of valvular dysfunction and arrhythmias; improved proteinuria; decreased urinary concentrations of lipids such as CTH, lactosylceramide, and ceramide, and increased urinary concentrations of glucosylceramide and sphingomyelin; absence of laminated inclusion bodies (zebra bodies) in glomerular epithelial cells; improved renal function; alleviation of hyperhidrosis; absence of angiokeratoma; and improvement in hearing abnormalities such as high-frequency sensorineural hearing loss, progressive hearing loss, sudden hearing loss, or tinnitus. Improvement in neurological symptoms includes prevention of transient ischemic attacks (TIA) or stroke, as well as amelioration of neuropathic pain manifested as acroparesthesia (burning or tingling in the extremities). The prevalence of adverse cardiovascular symptoms is another type of clinical marker that can be assessed in Fabry disease.

[0079] "Mid-wall fractional shortening" or "MWFS" is a measure of systolic function that identifies hypertensive patients with evidence of target organ damage, reduced contractile reserve, and increased mortality.

[0080] The term "cardiac function" refers to the performance of a patient's heart. For example, left ventricular systolic function (referring to the ejection characteristics of the left heart) is one assessment of cardiac function. Several methods for assessing left ventricular systolic function include, but are not limited to, left ventricular ejection fraction (LVEF), endocardial fractional shortening (EFS), and MWFS.

[0081] As used herein, the phrase "stabilizing cardiac function" and similar terms refer to reducing or arresting the decline in cardiac function and / or restoring cardiac function. Because untreated Fabry disease patients are expected to experience a significant decline in cardiac function over time, improving the rate of deterioration of cardiac function and / or enhancing cardiac function has been demonstrated to benefit from migalastat therapy as described herein. In various embodiments, stabilizing cardiac function includes stabilizing MWFS. Similarly, "stabilizing MWFS" refers to reducing or preventing a decrease in MWFS.

[0082] The term "enhancing cardiac function" refers to a beneficial change in at least one parameter used for the purpose of cardiac function evaluation. When a patient's parameter is at the lower end of the normal range or below the normal range of the parameter, a beneficial change in the parameter refers to an increase in the parameter. For example, in a patient with a low MWFS, an increase in MWFS refers to an enhancement of the parameter. Similarly, when a patient's parameter is at the upper end of the normal range or above the normal range of the parameter, a beneficial change in the parameter refers to a decrease in the parameter. In one embodiment, "enhancing cardiac function" includes one or more of: (i) improved left ventricular function, (ii) improved fractional shortening, (iii) improved ejection fraction, (iv) reduced end-diastolic volume, and (v) normalization of cardiac geometry.

[0083] As used herein, the term "MWFS disorder" refers to a patient whose MWFS is below the normal range. For women, the normal range for MWFS is considered to be at least 15%, and for men, the normal range for MWFS is considered to be at least 14%. Therefore, for female patients, MWFS disorder is considered to be less than 15%, and for male patients, MWFS disorder is considered to be less than 14%.

[0084] As used herein, the term "normalizing MWFS" refers to increasing a patient's MWFS from impaired MWFS to within the normal range. Thus, for female patients, normalizing MWFS refers to increasing MWFS from less than 15% to at least 15%, and for male patients, normalizing MWFS refers to increasing MWFS from less than 14% to at least 14%.

[0085] As used herein, the term "left ventricular hypertrophy" or "LVH" refers to a condition in which the left ventricular mass index (LVMi) is within the normal range (43-95 g / m in women). 2 , and 49-115g / m for men 2 ) in women. 2 >115 g / m for men 2 It means being super.

[0086] A dose that achieves one or more of the aforementioned responses is termed a "therapeutically effective amount."

[0087] The phrase "pharmaceutically acceptable" refers to physiologically acceptable molecular entities and compositions that do not normally produce adverse reactions when administered to humans. In some embodiments, the term "pharmaceutically acceptable" as used herein means approved by a federal or state regulatory agency or listed in the U.S. Pharmacopeia or other universally recognized pharmacopeia for use in animals, particularly humans. The term "carrier," referring to a pharmaceutical carrier, refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils. Water or aqueous saline solutions, as well as aqueous dextrose and glycerol solutions, are preferred carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in E.W. Martin's "Remington's Pharmaceutical Sciences," 18th Edition, or other editions.

[0088] As used herein, the term "isolated" means that the referenced material has been removed from the environment in which it is normally found. Thus, isolated biological material may be free of cellular components (i.e., components of the cell 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. More preferably, when found within a chromosome, they are no longer associated with non-regulatory, 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, and the like. Thus, in certain embodiments, recombinant nucleic acids are isolated nucleic acids. Isolated proteins may be associated with other proteins and / or nucleic acids to which they are associated within the cell, or, in the case of membrane-associated proteins, with the cell membrane. An isolated organelle, cell, or tissue is removed from the anatomical site it is found in. The isolated material can be purified, but need not be.

[0089] The term "enzyme replacement therapy" or "ERT" refers to the introduction of a non-naturally occurring purified enzyme into an individual lacking such an enzyme. The administered protein can be obtained from a natural source (as described in more detail below) or by recombinant expression. The term also refers to the introduction of a purified enzyme into an individual suffering from, for example, an enzyme deficiency, or otherwise requiring or benefiting from the administration of a purified enzyme. The introduced enzyme may be a purified recombinant enzyme produced in vitro, or it may be a purified protein derived from isolated tissues or body fluids, such as placenta or animal milk, or derived from plants.

[0090] The term "ERT-naive patients" refers to Fabry patients who have never received ERT or who have not received ERT for at least 6 months prior to initiating migalastat therapy.

[0091] The term "ERT-experienced patient" refers to a patient with Fabry disease who was receiving ERT immediately prior to initiating migalastat therapy. In some embodiments, an ERT-experienced patient has been receiving ERT for at least 12 months immediately prior to initiating migalastat therapy.

[0092] As used herein, the term "free base equivalent" or "FBE" refers to the amount of migalastat present in migalastat or its salt. 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, by weight of the hydrochloride salt, migalastat provided in 150 mg of migalastat hydrochloride is equivalent to 123 mg of migalastat in free base form. For other salts, the conversion factor is expected to vary depending on the molecular weight of the salt.

[0093] The term "migalastat," unless otherwise indicated to the contrary, includes migalastat free base or a pharmaceutically acceptable salt thereof (eg, migalastat HCl).

[0094] The terms "mutation" and "variant" (e.g., in the form of "adaptive mutation or variant") refer to a change in the nucleotide sequence of a gene or chromosome. These two terms are referred to herein and are typically used together, e.g., "mutation or variant," to refer to the change in the nucleotide sequence described above. If for any reason only one of these two terms is recited, it should be understood that the missing term was intended to be included. Furthermore, the terms "adaptive mutation" and "adaptive mutation" refer to a mutation or variant, such as a mutation that is adaptive to PC therapy, e.g., migalastat therapy. A particular type of adaptive mutation or variant is a "HEK assay adaptive mutation or variant," which is a mutation or variant that is determined to be adaptive to migalastat therapy according to the criteria of the in vitro HEK assay described herein and in U.S. Patent No. 8,592,362, the entire contents of which are incorporated herein by reference.

[0095] 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. Exemplary degrees of error are typically 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, preferably within 10-fold or within 5-fold, and more preferably within 2-fold, of a given value. Numerical values ​​given herein are approximate unless otherwise stated, meaning that the term "about" or "approximately" can be inferred unless expressly stated.

[0096] Fabry disease Fabry disease is a rare, progressive, and devastating X-linked LSD. Mutations in the GLA gene result in a deficiency of the lysosomal enzyme α-Gal A, which is required for glycosphingolipid metabolism. Reduced α-Gal A activity, beginning at an early age, results in the accumulation of glycosphingolipids, including GL-3 and plasma lysoGb3, which leads to the symptoms and life-limiting sequelae of Fabry disease, such as 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.

[0097] Fabry disease encompasses a spectrum of disease severity and age of onset, but has traditionally been divided into two major phenotypes: "classic" and "late-onset." The classic phenotype has been attributed primarily to men with undetectable to low α-Gal A activity and early-onset renal, cardiac, and / or cerebrovascular manifestations. The late-onset phenotype has been attributed primarily to men with high residual α-Gal A activity and late-onset disease manifestations. Heterozygous female carriers usually manifest the late-onset phenotype, but depending on the pattern of X-chromosome inactivation, some may also exhibit a more classic phenotype.

[0098] Over 1,000 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 unstable, misfolded forms of α-Gal A, the majority of which are associated with the classic phenotype. Normal cellular quality control mechanisms in the ER block trafficking of these abnormal proteins to lysosomes, targeting them for early degradation and removal. Many missense mutant forms are targeted by migalastat, an α-Gal A-specific pharmacological chaperone.

[0099] The clinical manifestations of Fabry disease range in severity and correlate roughly with the patient's residual α-Gal A levels. The majority of patients currently receiving treatment are referred to as classic Fabry disease patients, the majority of whom are men. These patients experience disease affecting various organs, including the kidneys, heart, and brain. Symptoms of the disease first appear during adolescence, typically progressing in severity and eventually resulting in death in the patient's third or fourth decade. Numerous recent studies suggest that a range of Fabry disease symptoms, such as cardiac or renal dysfunction and stroke, usually first appear in adulthood, yet many men and women remain undiagnosed. Individuals with this form of Fabry disease, referred to as late-onset Fabry disease, tend to have higher residual α-Gal A levels than classic Fabry disease patients. Individuals with late-onset Fabry disease most commonly first experience disease symptoms in adulthood, often with disease manifestations focused on a single organ, such as left ventricular hypertrophy or progressive renal failure. In addition, late-onset Fabry disease can also manifest in the form of strokes of unknown etiology.

[0100] Patients with Fabry disease suffer from progressive renal dysfunction, and untreated individuals develop end-stage renal disease by their fourth decade. Deficiency of α-Gal A activity results in the accumulation of GL-3 and related glycosphingolipids in many cell types, including those within the kidney. GL-3 accumulates in podocytes, epithelial cells, and tubular cells in the distal tubule and loop of Henle. Impaired renal function manifests as proteinuria and a decreased glomerular filtration rate.

[0101] Fabry disease is rare, involves multiple organs, has a wide age range for onset, and is heterogeneous, making proper diagnosis challenging. Awareness among medical professionals is low, leading to frequent misdiagnosis. Once a patient becomes symptomatic, the diagnosis of Fabry disease is confirmed based on reduced plasma or peripheral white blood cell (WBC) α-Gal A activity, frequently in conjunction with mutation analysis. In females, diagnosis is further complicated by the unreliability of enzymatic identification of female carriers due to random X-chromosome inactivation in some cells of carriers. For example, some obligate carriers (daughters of classically affected men) have α-Gal A enzyme activity ranging from normal to extremely low activity. Because carriers can have normal α-Gal A enzyme activity in their white blood cells, accurate carrier identification and / or diagnosis is limited to the identification of α-Gal A mutations by genetic testing.

[0102] In one or more embodiments, when a mutant form of α-Gal A is expressed in HEK-293 cells (referred to as the "HEK assay") according to a Good Laboratory Practice (GLP) validated in vitro assay (the GLP HEK or migalastat adaptability assay), the mutant form of α-Gal A is considered migalastat adaptable, exhibiting a relative increase (+10 μM migalastat) of greater than 1.20-fold and an absolute increase (+10 μM migalastat) of greater than 3.0% over wild-type (WT). Such mutations are also referred to herein as "HEK assay adaptable" mutations.

[0103] Conventional screening methods are available to assess enzyme enhancement prior to initiation of treatment. For example, an assay using HEK-293 cells has been utilized in clinical trials aimed at predicting 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 in cell lysates are then measured using a synthetic fluorescent 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 using these methods as responsive to PC (e.g., migalastat) are described in U.S. Patent No. 8,592,362.

[0104] Pharmacological Chaperones Binding small molecule inhibitors of LSD-related enzymes can enhance the stability of both mutant and 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). In particular, administration of small molecule derivatives of glucose and galactose, which are specific and selective competitive inhibitors of several target lysosomal enzymes, effectively enhanced the stability of cellular enzymes in vitro, thereby increasing the trafficking of the enzymes to lysosomes. Therefore, increasing the amount of enzyme in lysosomes is expected to enhance the hydrolysis of enzyme substrates. The rationale behind this strategy was that mutant enzyme proteins are unstable in the ER (Ishii et al., Biochem. Biophys. Res. Comm. 1996;220:812-815), resulting in delays in the normal transport pathway (ER → Golgi apparatus → endosomes → lysosomes) and premature degradation. Therefore, compounds that bind to and enhance the stability of mutant enzymes act as "chaperones" for the enzymes, allowing increased amounts of the enzyme to exit the ER and traffic to lysosomes. In addition, the folding and trafficking of some wild-type proteins is defective, and up to 70% of some wild-type proteins are degraded before reaching their final cellular location. For this reason, chaperones may be used to stabilize wild-type enzymes, thereby increasing the amount of enzyme that can exit the ER and traffic to lysosomes.

[0105] 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)piperidine-3,4,5-triol, is a compound having the following chemical formula: TIFF0007755929000001.tif39170 Migalastat free base

[0106] As discussed herein, pharmaceutically acceptable salts of migalastat can also be used in the present invention. When using a salt of migalastat, the dosage of the salt is adjusted so that the dosage of migalastat administered to a patient is equivalent to the dosage when migalastat free base is used. An example of a pharmaceutically acceptable salt of migalastat is migalastat HCl. TIFF0007755929000002.tif38170 Migalastat HCl

[0107] 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, selectively and reversibly binding with high affinity to wild-type α-Gal A and specific mutant forms of α-Gal A with genotypes designated HEK assay adaptive mutations at the active site. Migalastat binding stabilizes these mutant forms of α-Gal A within the endoplasmic reticulum and promotes their proper trafficking to lysosomes, where dissociation of migalastat allows α-Gal A to reduce levels of GL-3 and other substrates. Approximately 30-50% of patients with Fabry disease have HEK assay adaptive mutations, the majority of which are associated with the classic phenotype of the disease.

[0108] HEK assay adaptive mutations include at least those mutations listed in a pharmacological reference table (e.g., those listed in the U.S. or international product labeling of a migalastat product, such as GALAFOLD®). As used herein, a "pharmacological reference table" refers to a publicly accessible document or electronic record contained either in the product labeling in the migalastat product packaging (e.g., GALAFOLD®) or on a website accessible to healthcare providers. This pharmacological reference table communicates whether a particular mutation or variant will respond to migalastat (e.g., GALAFOLD®) PC therapy and is not necessarily limited to a written record presented in tabular format. Thus, in one embodiment of the present invention, a "pharmacological reference table" refers to any repository of information listing one or more adaptive mutations or variants. Exemplary pharmacological reference tables of HEK assay adaptive mutations can be found in the Summary of Product Characteristics in the various countries where GALAFOLD® is approved for use and / or in the GALAFOLD® prescribing information, or on websites such as www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com, each of which is incorporated herein by reference in its entirety.

[0109] Table 1 below provides an exemplary pharmacological reference table of HEK assay-adaptive mutations. In one or more embodiments, a patient is considered HEK assay-adaptive if the double mutation is present in one entry of Table 1 (e.g., D55V / Q57L), provided that the double mutation is present on the same chromosome (male and female). In some embodiments, a patient is considered HEK assay-adaptive if either of the individual mutations in Table 1 is present, provided that the double chromosomal mutation is present on a different chromosome (females only). TIFF0007755929000003.tif254170TIFF0007755929000004.tif254170TIFF0007755929000005.tif254170TIFF0007755929000006.tif255170 TIFF0007755929000007.tif255170TIFF0007755929000008.tif254170TIFF0007755929000009.tif254170TIFF0007755929000010.tif228170

[0110] Medication, prescription and administration In one or more embodiments, migalastat or a salt thereof is administered to patients with Fabry disease once every other day (also known as "QOD"). In various embodiments, the doses described herein relate to migalastat hydrochloride, or an equivalent dose of migalastat or a salt thereof (but other than the hydrochloride salt). In some embodiments, the doses relate to the free base of migalastat. In alternative embodiments, the 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."

[0111] An effective amount of migalastat or a salt thereof may range from about 100 mg FBE to about 150 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, or about 150 mg FBE.

[0112] It should be noted again that 150 mg of migalastat hydrochloride is equivalent to 123 mg of migalastat in its free base form. Thus, in one or more embodiments, the dose is 150 mg of migalastat hydrochloride, or an equivalent dose of migalastat or a salt thereof (other than the hydrochloride salt), administered once every other day. As noted 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.

[0113] In various embodiments, an effective amount of migalastat hydrochloride 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, or about 183 mg.

[0114] Thus, in various embodiments, migalastat therapy includes administering 123 mg FBE once every other day, eg, 150 mg migalastat hydrochloride every other day.

[0115] The administration of migalastat or a salt thereof may be for a certain period of time. In one or more embodiments, the migalastat or a salt thereof is administered for at least 28 days, for example, at least 30, 60, or 90 days, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30, or 36 months, or at least 1, 2, 3, 4, or 5 years. In various embodiments, the migalastat therapy is long-term migalastat therapy for at least 6 months, for example, at least 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30, or 36 months, or at least 1, 2, 3, 4, or 5 years.

[0116] The migalastat or a salt thereof according to the present invention can be administered in a formulation suitable for any route of administration, but is preferably administered in an oral dosage form such as a tablet, capsule, or liquid. By way of example, each capsule administered orally to a patient contains 150 mg of migalastat hydrochloride, or an equivalent dose of migalastat or a salt thereof (other than the hydrochloride salt).

[0117] 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 vary depending on the method of administration.

[0118] In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered as monotherapy and can be in a form suitable for any route of administration, including oral administration, for example, in tablet or capsule form, or in liquid form, or in a sterile aqueous solution for injection. In other embodiments, the PC is provided as a dry lyophilized powder and is added to the replacement enzyme formulation during or shortly after reconstitution to prevent enzyme aggregation in vitro prior to administration.

[0119] When PC (e.g., migastat or its salt) is formulated for oral administration, tablets or capsules can be prepared by conventional means. Pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); 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), can be used. Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, a solution, syrup, or suspension, or can be presented as a dry product that is to be reconstituted with water or another suitable vehicle before use. Such liquid preparations may be prepared by conventional means using 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-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavoring agents, coloring agents, and sweetening agents, as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active chaperone compound.

[0120] Pharmaceutical formulations of PC (e.g., migastat or its salts) suitable for parenteral / injectable use generally include sterile aqueous solutions (if water soluble) or dispersions, and sterile powders (for the extemporaneous preparation of sterile injectable solutions or dispersions). In all cases, the form must be sterile and fluid to the extent that easy syringability exists. The form 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 may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Means for maintaining proper fluidity include, for example, the use of a coating such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. The action of microorganisms can be prevented 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 injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0121] To prepare sterile injectable solutions, the purified enzyme (if present) and PC (e.g., migalastat or its salts) are incorporated into a suitable solvent, as needed, along with various other ingredients listed above, and then subjected to filter sterilization or terminal sterilization. Generally, to prepare dispersions, various sterilized active ingredients are incorporated into a sterile vehicle containing a basic dispersion medium and other necessary ingredients (listed above). In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method is vacuum drying and freeze-drying technology. This preparation method yields not only a powder of the active ingredient but also any additional desired ingredients from the previously sterile-filtered solution.

[0122] The formulation may contain an excipient. Pharmaceutically acceptable excipients that can be included in the formulation include buffers such as citrate buffer, phosphate buffer, acetate buffer, bicarbonate buffer, amino acids, urea, alcohol, ascorbic acid, and phospholipids; proteins such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA and sodium chloride; liposomes; polyvinylpyrrolidone; 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 preferred in some embodiments.

[0123] The route of administration of the chaperone compound may be oral or parenteral, such as intravenous, subcutaneous, intra-arterial, intraperitoneal, intraocular, intramuscular, buccal, rectal, vaginal, intraorbital, intracerebral, intradermal, intracranial, intraspinal, intraventricular, intrathecal, intracisternal, intravesicular, intrapulmonary, intranasal, transmucosal, transdermal, or via inhalation.

[0124] The above parenteral formulations of the chaperone compound may be administered by periodic injection of a bolus of the formulation, or by intravenous or intraperitoneal administration from an external (e.g., intravenous bag) or internal (e.g., bioerodible implant) reservoir.

[0125] Embodiments relating to pharmaceutical formulations and administration can be combined with any of the other embodiments of the invention, such as methods of treating Fabry disease patients, methods of treating ERT-naive Fabry patients, methods of treating ERT-experienced Fabry patients, methods of enhancing cardiac function (e.g., left ventricular systolic function), methods of stabilizing cardiac function (e.g., left ventricular systolic function), methods of increasing MWFS, methods of stabilizing MWFS, methods of normalizing MWFS, methods of enhancing α-Gal A in patients diagnosed with or suspected of having Fabry disease, use of a pharmacological chaperone for α-Gal A for the manufacture of a medicament for the treatment of patients diagnosed with Fabry disease, or use of a pharmacological chaperone for α-Gal A for the treatment of patients diagnosed with Fabry disease, as well as embodiments relating to adaptive mutations, PCs, and suitable dosages thereof.

[0126] In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered in combination with ERT. ERT enhances the amount of a protein by exogenously introducing a wild-type or biologically functional enzyme via infusion. This therapy has been developed to address many genetic disorders, including LSDs such as the previously mentioned Fabry disease. After infusion, the exogenous enzyme is expected to be taken up by 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 and prone to rapid intracellular degradation, potentially resulting in adverse immunological reactions following subsequent treatment. In one or more embodiments, a chaperone is administered simultaneously with the replacement enzyme (e.g., substituted α-Gal A). In some embodiments, the chaperone is co-formulated with the replacement enzyme (e.g., substituted α-Gal A).

[0127] In one or more embodiments, the patient is switched from ERT to migalastat therapy. In some embodiments, an ERT-experienced patient is identified, the patient is discontinued from ERT, and the patient begins migalastat therapy. The migalastat therapy may be according to any of the methods described herein.

[0128] Heart function The dosing regimens described herein enable stabilization and / or enhancement of cardiac function (e.g., left ventricular systolic function) in Fabry patients. Untreated Fabry patients typically experience a deterioration in cardiac function over time, suggesting that both enhancement and maintenance of cardiac function are benefits of migalastat therapy. As further detailed in the Examples below, Phase 3 studies have found that migalastat therapy increases and / or stabilizes MWFS in both ERT-experienced and ERT-naive patients. These Phase 3 studies have also found that migalastat therapy normalizes MWFS in patients with impaired MWFS. Thus, migalastat therapy can be used to treat Fabry patients by stabilizing MWFS, increasing MWFS, and / or normalizing MWFS in ERT-naive and / or ERT-experienced Fabry patients, including those with impaired MWFS.

[0129] Migalastat therapy can halt or reduce the decline in MWFS and / or increase MWFS in patients with Fabry disease compared to the same patient not treated with migalastat therapy. In one or more embodiments, migalastat therapy can result in a patient's MWFS change of more than -2% (i.e., greater than -2% positive), such as about -1.5% or more, -1.4%, -1.3%, -1.2%, -1.1%, -1%, -0.9%, -0.8%, -0.7%, -0.6%, -0.5%, -0.4%, -0.3%, In one or more embodiments, the Fabry patient is an ERT-experienced patient. In one or more embodiments, the Fabry patient is an ERT-naive patient. In one or more embodiments, the Fabry patient has MWFS disorder prior to initiation of migalastat therapy. do .

[0130] In one or more embodiments, migalastat therapy results in a mean change in MWFS of at least about 0% in an ERT-naive patient population after 12 months of administration of migalastat or a salt thereof. In various embodiments, after 12 months of administration of migalastat or a salt thereof, the mean increase in an ERT-naive patient population is at least about 0.05%, about 0.1%, about 0.15%, or about 0.2%. In one or more embodiments, the ERT-naive patient has an MWFS disorder prior to initiation of migalastat therapy. do .

[0131] In one or more embodiments, migalastat therapy results in a mean change in MWFS of at least about 0% in ERT-naive patients after 24 months of administration of migalastat or a salt thereof. In various embodiments, the mean increase in ERT-naive patients 12 months after administration of migalastat or a salt thereof is at least about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5%. In one or more embodiments, the ERT-naive patient has impaired MWFS prior to initiation of migalastat therapy. do .

[0132] In one or more embodiments, migalastat therapy results in a mean change in MWFS of at least about 0% in ERT-naive patients after 36 months of administration of migalastat or a salt thereof. In various embodiments, the mean increase in ERT-naive patients 12 months after administration of migalastat or a salt thereof is at least about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, or about 1.5%. In one or more embodiments, the ERT-naive patient has an MWFS disorder prior to initiation of migalastat therapy. do .

[0133] In one or more embodiments, migalastat therapy results in a mean change in MWFS of at least about 0% in an ERT-naive patient population after 48 months of administration of migalastat or a salt thereof. In various embodiments, the mean increase in an ERT-naive patient population 12 months after administration of migalastat or a salt thereof is at least about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, or about 2.5%. In one or more embodiments, the ERT-naive patient has MWFS disorder prior to initiation of migalastat therapy. do .

[0134] In one or more embodiments, migalastat therapy results in a mean change in MWFS of greater than about -1.5% in ERT-naive patients after 30 months of administration of migalastat or a salt thereof. In various embodiments, the mean increase in ERT-naive patients 12 months after administration of migalastat or a salt thereof is greater than -1.5%, greater than -1.4%, greater than -1.3%, greater than -1.2%, greater than -1.1%, greater than -1%, greater than -0.9%, greater than -08%, greater than -0.7%, greater than -0.6%, greater than -0.5%, greater than -0.4%, greater than -0.3%, greater than -0.2%, greater than -0.1%, or greater than 0%. In one or more embodiments, the ERT-experienced patient has MWFS impairment prior to initiation of migalastat therapy. do . [Example]

[0135] Example 1: Dosing regimen for treating ERT-naive Fabry patients Use of migalastat hydrochloride This example describes a phase 3 trial of migalastat therapy in ERT-naive Fabry patients.

[0136] Patient Enrollment. Eligible patients were 16 to 74 years old and had genetically confirmed Fabry disease. They had never received ERT or had not received ERT for >6 months. They had a GLA mutation resulting in a mutant protein that responded to migalastat based on the human embryonic kidney-293 (HEK) assay used at enrollment; eGFR was 30 ml / min / 1.73 m. 2 and urinary GL-3 was more than four times the upper limit of normal.

[0137] Study Design: After a baseline eligibility assessment (2 months), patients were randomized to Stage 1, where they received double-blind treatment with migalastat hydrochloride 150 mg or placebo every other day for 6 months. All patients who completed Stage 1 were eligible for Stage 2 (6-12 months) and then open-label migalastat for an additional year (13-24 months). The primary objective was to compare the effects of migalastat and placebo on renal GL-3, as assessed by histological scoring of the number of inclusion bodies in interstitial capillaries, after 6 months of treatment. Secondary objectives of Stage 1 were to compare the effects of migalastat and placebo on urinary GL-3 levels, renal function, 24-hour urinary protein, and safety and tolerability. Tertiary objectives included cardiac function, patient-reported outcomes, exploratory renal analyses, and leukocyte α-Gal A activity. Study completers were eligible to enroll in an open-label extension study for up to 5 years.

[0138] Renal tissue assessment. Each patient underwent a baseline renal biopsy and repeat renal biopsies at 6 and 12 months. The number of GL-3 inclusions per renal interstitial capillary for each patient at baseline and at 6 and 12 months was quantitatively assessed in 300 capillaries by three independent pathologists blinded to treatment and visits. All values ​​from individual biopsies at a given time point were averaged prior to statistical analysis.

[0139] GL-3 changes in podocytes, endothelial cells, and mesangial cells, and glomerular sclerosis were qualitatively assessed by the same three pathologists blinded to treatment / visit.

[0140] Globotriaosylceramide and globotriaosylsphingosine. Plasma lyso-Gb3 and 24-hour urinary GL-3 were analyzed by liquid chromatography-mass spectrometry using a novel stable isotope-labeled internal standard, 13C6-lyso-Gb3 (lower limits of quantitation: 0.200 ng / mL, 0.254 nmol / L).

[0141] Evaluation of renal function. Chronic Kidney Disease Epidemiology Collaborative Study (eGFR CKD-EPI ) to calculate the annual rate of change (mL / min / 1.73m 2 / year) was calculated and iohexol clearance (mGFRiohexol) was measured.

[0142] Echocardiography. LVMi, left posterior wall thickness, diastole, interventricular septal thickness, diastole, and other parameters were assessed by blinded central evaluation.

[0143] Patient-reported outcomes. Patient-reported outcomes were assessed using the Gastrointestinal Symptom Rating Scale (GSRS), Short Form-36v2™, and Brief-Pain-Inventory-Pain-Severity-Component.

[0144] Safety Analyses and Adverse Events. Safety analyses included randomized patients receiving more than one dose of medication, including vital signs, physical examination, electrocardiogram, laboratory tests, and adverse events.

[0145] Statistical Analysis of Renal Interstitial Capillary GL-3 Substrate. The primary Stage 1 (6-month) endpoint (ITT population with baseline biopsy, n=64) was the proportion of patients in the migalastat and placebo groups with a GL-3 inclusion reduction per interstitial capillary of >50%. Two other Stage 1 endpoints (modified ITT population: randomized patients with combined baseline and 6-month biopsies; n=60): percent change in GL-3 inclusions per interstitial capillary and percent interstitial capillaries with zero GL-3 inclusions were assessed.

[0146] Efficacy analyses of GL-3 inclusions per interstitial capillaries and other prespecified endpoints in Stage 2 (months 6-12) and open-label extension (months 12-24) were based on a modified intention-to-treat (mITT) approach. The randomized population consisted of patients with mutant α-Gal A enzyme who were identified as suitable for migalastat treatment by a validated assay (n=50).

[0147] result Baseline Characteristics. Sixty-seven patients (16-74 years old, 64% female) with potentially responsive mutant α-Gal A were randomized (ITT population). Table 2 shows the baseline characteristics of the 50 patients in the ITT population with favorable mutant α-Gal A. There were no statistically significant differences in baseline parameters. TIFF0007755929000011.tif210170

[0148] Published reports of genotype-associated clinical phenotype(s) in patients with favorable mutations (n=50) suggest that 30 patients (60%) had mutations associated with the classic phenotype of Fabry disease, 1 patient (2%) had a nonclassic phenotype, 3 patients (6%) had both phenotypes, and 16 patients (32%) were unclassified. Residual WBC α-Gal A activity less than 3% was found in 14 of 16 (87%) males. Elevated plasma lysoGb3 was present in 29 of 31 (94%) males and women, and multisystem disease was present in 47 of 50 (94%) males and women.

[0149] Baseline MWFS. Impaired MWFS was reported in 9 patients at baseline (<15% in women and <14% in men).

[0150] Migalastat and Cardiac Function. This study in ERT-naive patients found that migalastat therapy increased MWFS in patients with impaired MWFS at baseline. Table 3 below shows the change in MWFS relative to baseline after migalastat therapy. TIFF0007755929000012.tif74170Last observation carried forward (LOCF) analyses were based on the last study assessment, including unscheduled visits or early termination of visits. MWFS abnormalities were less than 15% in women and less than 14% in men.

[0151] As can be seen in Table 3, LOCF analysis of ERT-naive patients with impaired MWFS at baseline revealed a mean change in MWFS of 1.9% (95% CI: -0.8%, 4.5%; n = 8) with 48 months of migalastat therapy. Six of eight patients (75%) demonstrated an increase in MWFS after migalastat therapy, and three of eight patients (38%) demonstrated normalization of MWFS.

[0152] Patients with baseline LVH were also included in the MWFS analysis. The change in MWFS from baseline in patients with baseline LVH is shown in Table 4 below. TIFF0007755929000013.tif71170LOCF analysis was based on the final study assessment, including unscheduled visits or early termination of visits. In the LVH subgroup, LVMi > 95 g / m 2 Ultra (women) or 115g / m 2 He was super (male).

[0153] As can be seen in Table 4, LOCF analysis of ERT-naive patients with baseline LVH demonstrated a mean change in MWFS of 1.0% (95% CI: -1.5%, 3.5%; n = 10) with migalastat therapy over 48 months. Seven of 10 patients (70%) demonstrated an increase in MWFS after migalastat therapy, and two of 10 patients (20%) demonstrated normalization of MWFS.

[0154] Safety and Adverse Events. During Stage 1, treatment-emergent adverse events were similar between groups. In patients receiving migalastat compared with placebo, more frequent adverse events were headache (12 of 34 patients (35%) vs. 7 of 33 patients (21%)) and nasopharyngitis (6 of 34 patients (18%) vs. 2 of 34 patients (6%)). In Stage 2, the most frequently reported adverse events were headache (9 of 63 patients (14%)) and renal biopsy-related procedural pain (7 of 63 patients (11%)); in the open-label extension, they were proteinuria (9 of 57 patients (16%)), headache (6 of 57 patients (11%)), and bronchitis (6 of 57 patients (11%)). Most adverse events were mild or moderate in severity. No adverse events led to discontinuation of migalastat.

[0155] Six patients experienced serious adverse events during Stage 1 (two migalastat, four placebo), five during Stage 2, and 11 during the open-label extension. The two most serious adverse events considered related to migalastat, fatigue and paresthesia, were assessed by the investigator. Both occurred in the same patient between months 12 and 24 and resolved. No individual serious adverse event was reported by more than one patient. Two patients discontinued migalastat due to serious adverse events, both of which were considered unrelated to migalastat. No deaths were reported.

[0156] Treatment-emergent proteinuria was reported in nine patients (16%) between months 12 and 24, and in one case was determined to be migalastat-related. In five patients, the 24-month values ​​were in the same range as baseline. Three patients with favorable mutations had overt baseline proteinuria (>1 g / 24 h), which increased over 24 months. During migalastat treatment, 23 of 28 patients with baseline proteinuria <300 mg / 24 h maintained stable urinary protein levels over 24 hours.

[0157] There were no progression to end-stage renal disease, cardiac death, or stroke as defined by Banikazemi et al. There was a single case of transient ischemic attack, but it was determined to be unrelated to migalastat.

[0158] Analysis of vital signs, physical examination, laboratory, and ECG parameters did not reveal any clinically relevant effects of migalastat.

[0159] Example 2: Dosing regimen for treating ERT-experienced patients with Fabry disease using migalastat hydrochloride This example describes a phase 3 trial of migalastat therapy in ERT-experienced Fabry patients.

[0160] Patient Enrollment. Eligible patients were 16 to 74 years of age and had genetically confirmed Fabry disease. They had been receiving ERT for >12 months. They had a GLA mutation resulting in a mutant protein that responded to migalastat based on the human embryonic kidney-293 (HEK) assay used at enrollment; eGFR ≥ 30 ml / min / 1.73 m 2 exceeded; ERT dose level and regimen remained stable for at least 3 months.

[0161] Study design: After baseline eligibility assessment, 57 patients were randomly assigned to receive either 18 months of migalastat therapy or ERT followed by 12 months of migalastat therapy. The migalastat dosing regimen was 150 mg of migalastat hydrochloride every other day. The primary objective was to achieve mGFR after 18 months of treatment. iohexol The aim of this study was to compare the effect of migalastat with ERT on renal function as assessed by urinary tract infection (ERT).Secondary objectives were to compare the effects of migalastat and ERT on: renal function (assessed by eGFR and 24-hour urinary protein); composite clinical outcome (assessed by time to renal, cardiac, cerebrovascular event or death); cardiac function (assessed by echocardiography) and patient-reported outcomes (pain and quality of life).

[0162] Baseline MWFS. Impaired MWFS (<15% in women, <14% in men) was reported at baseline in 19 patients (14 migalastat, 5 ERT).

[0163] result Migalastat and Cardiac Function. In this study of ERT-experienced patients, migalastat therapy was found to stabilize MWFS in patients with impaired MWFS at baseline. As determined by LOCF analysis of patients with impaired MWFS at baseline, the mean change from baseline over 30 months of migalastat therapy was -0.2% (95% CI: -1.3%, 1.0%; n = 14). As determined by LOCF analysis of patients with impaired MWFS, the mean change from baseline MWFS over 18 months of therapy on ERT was -0.6% (95% CI: -2.6%, 1.4%; n = 5).

[0164] The embodiments described herein are intended to illustrate the compositions and methods of the present invention and are not intended to limit the scope of the present invention. Various modifications and variations have been described, and it is intended that they be consistent with the entire description and be readily apparent to those skilled in the art. The scope of the appended claims should not be limited to the specific embodiments described in the examples, but should be accorded the broadest interpretation consistent with the entire description.

[0165] Patents, patent applications, publications, product descriptions, GenBank accession numbers, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entirety for all purposes. Further embodiments of the present invention [Embodiment 1] A method for enhancing cardiac function in a patient with Fabry disease, comprising administering to the patient every other day a formulation containing an effective amount of migalastat or a salt thereof for the purpose of enhancing cardiac function in the patient, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE). [Embodiment 2] 2. The method of embodiment 1, wherein enhancing cardiac function includes enhancing left ventricular systolic function. [Embodiment 3] 3. The method of embodiment 1 or 2, wherein the patient had midwall left ventricular fractional shortening (MWFS) impairment prior to initiation of administration of migalastat or a salt thereof. [Embodiment 4] 4. The method according to any one of embodiments 1 to 3, wherein said migalastat or a salt thereof enhances α-galactosidase A activity. [Embodiment 5] 5. The method according to any one of embodiments 1 to 4, wherein said patient is administered about 123 mg FBE of said migalastat or a salt thereof every other day. [Embodiment 6] 6. The method of any one of embodiments 1-5, wherein said patient is administered about 123 mg of migalastat free base every other day. [Embodiment 7] 6. The method of any one of embodiments 1 to 5, wherein said patient is administered about 150 mg of migalastat hydrochloride every other day. [Embodiment 8] 8. The method of any one of embodiments 1 to 7, wherein the formulation comprises an oral dosage form. [Embodiment 9] 9. The method of embodiment 8, wherein the oral dosage form comprises a tablet, capsule, or liquid. [Embodiment 10] 10. The method according to any one of embodiments 1 to 9, wherein the migalastat or a salt thereof is administered for at least 12 months. [Embodiment 11] 11. The method according to any one of embodiments 1 to 10, wherein the migalastat or a salt thereof is administered for at least 24 months. [Embodiment 12] 12. The method according to any one of embodiments 1 to 11, wherein said patient is an enzyme replacement therapy (ERT) naive patient. [Embodiment 13] 13. The method of any one of embodiments 1-12, wherein administration of migalastat or a salt thereof results in a mean increase in MWFS of at least about 1% in a group of ERT-naive patients with MWFS disorders after the administration of migalastat or a salt thereof for 24 months. [Embodiment 14] 12. The method according to any one of embodiments 1 to 11, wherein the patient is an ERT-experienced patient. [Embodiment 15] 15. The method of any one of embodiments 1 to 14, wherein the patient has a HEK assay-adaptive mutation in alpha-galactosidase A. [Embodiment 16] 16. The method of embodiment 15, wherein the mutation is disclosed in a pharmacological reference table. [Embodiment 17] 17. The method of embodiment 16, wherein the pharmacological reference table is provided in the product label of a migalastat product approved for the treatment of Fabry disease. [Embodiment 18] 17. The method of embodiment 16, wherein the pharmacological reference table is provided in the GALAFOLD® product label. [Embodiment 19] 17. The method of embodiment 16, wherein the pharmacological reference table is provided on a website. [Embodiment 20] 20. The method of embodiment 19, wherein the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com. [Embodiment 21] A method for increasing midwall left ventricular fractional shortening (MWFS) in a patient with Fabry disease, comprising administering to the patient every other day a formulation containing an effective amount of migalastat or a salt thereof for the purpose of increasing the patient's MWFS, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE). [Embodiment 22] 22. The method of embodiment 21, wherein the patient had MWFS disorder prior to initiation of administration of the migalastat or salt thereof. [Embodiment 23] 23. The method of embodiment 21 or 22, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. [Embodiment 24] 24. The method according to any one of embodiments 21 to 23, wherein the patient is administered about 123 mg FBE of the migalastat or salt thereof every other day. [Embodiment 25] 25. The method of any one of embodiments 21-24, wherein the patient is administered about 123 mg of migalastat free base every other day. [Embodiment 26] 25. The method of any one of embodiments 21 to 24, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. [Embodiment 27] 27. The method of any one of embodiments 21-26, wherein the formulation comprises an oral dosage form. [Embodiment 28] 28. The method of embodiment 27, wherein the oral dosage form comprises a tablet, capsule, or liquid. [Embodiment 29] 29. The method according to any one of embodiments 21 to 28, wherein the migalastat or a salt thereof is administered for at least 12 months. [Embodiment 30] 30. The method according to any one of embodiments 21 to 29, wherein the migalastat or a salt thereof is administered for at least 24 months. [Embodiment 31] 31. The method according to any one of embodiments 21 to 30, wherein the patient is an enzyme replacement therapy (ERT) naive patient. [Embodiment 32] 32. The method of any one of embodiments 21 to 31, wherein administration of migalastat or a salt thereof results in a mean increase in MWFS of at least about 1% in a group of ERT-naive patients with MWFS disorders after the administration of migalastat or a salt thereof for 24 months. [Embodiment 33] 31. The method according to any one of embodiments 21 to 30, wherein the patient is an ERT-experienced patient. [Embodiment 34] 34. The method of any one of embodiments 21 to 33, wherein the patient has a HEK assay-adaptive mutation in alpha-galactosidase A. [Embodiment 35] 35. The method of embodiment 34, wherein the mutation is disclosed in a pharmacological reference table. [Embodiment 36] 36. The method of embodiment 35, wherein the pharmacological reference table is provided in the product label of a migalastat product approved for the treatment of Fabry disease. [Embodiment 37] 36. The method of embodiment 35, wherein the pharmacological reference table is provided in the GALAFOLD® product label. [Embodiment 38] 36. The method of embodiment 35, wherein the pharmacological reference table is provided on a website. [Embodiment 39] The method of embodiment 38, wherein the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com. [Embodiment 40] A method for normalizing midwall left ventricular fractional shortening (MWFS) in a patient with Fabry disease and MWFS disorder, the method comprising administering to the patient every other day a formulation containing an effective amount of migalastat or a salt thereof for the purpose of normalizing the patient's MWFS, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE). [Embodiment 41] 41. The method of embodiment 40, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. [Embodiment 42] 42. The method of embodiment 40 or 41, wherein the patient is administered about 123 mg FBE of the migalastat or salt thereof every other day. [Embodiment 43] 43. The method of any one of embodiments 40-42, wherein the patient is administered about 123 mg of migalastat free base every other day. [Embodiment 44] 43. The method of any one of embodiments 40 to 42, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. [Embodiment 45] 45. The method of any one of embodiments 40 to 44, wherein the formulation comprises an oral dosage form. [Embodiment 46] 46. ​​The method of embodiment 45, wherein the oral dosage form comprises a tablet, capsule, or liquid. [Embodiment 47] 47. The method according to any one of embodiments 40 to 46, wherein the migalastat or a salt thereof is administered for at least 12 months. [Embodiment 48] 48. The method according to any one of embodiments 40 to 47, wherein the migalastat or a salt thereof is administered for at least 24 months. [Embodiment 49] 49. The method according to any one of embodiments 40 to 48, wherein the patient is an enzyme replacement therapy (ERT) naive patient. [Embodiment 50] 50. The method of any one of embodiments 40-49, wherein administration of migalastat or a salt thereof results in a mean increase in MWFS of at least about 1% in a group of ERT-naive patients with MWFS disorders after the administration of migalastat or a salt thereof for 24 months. [Embodiment 51] 51. The method of any one of embodiments 40 to 50, wherein the patient has a HEK assay-adaptive mutation in alpha-galactosidase A. [Embodiment 52] 52. The method of embodiment 51, wherein the mutation is disclosed in a pharmacological reference table. [Embodiment 53] 53. The method of embodiment 52, wherein the pharmacological reference table is provided in the product label of a migalastat product approved for the treatment of Fabry disease. [Embodiment 54] The method of embodiment 52, wherein the pharmacological reference table is provided in the GALAFOLD® product label. [Embodiment 55] 53. The method of embodiment 52, wherein the pharmacological reference table is provided on a website. [Embodiment 56] 56. The method of embodiment 55, wherein the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com. [Embodiment 57] A method for stabilizing midwall left ventricular fractional shortening (MWFS) in a patient with Fabry disease who has undergone enzyme replacement therapy (ERT), the method comprising administering to the patient every other day a formulation containing an effective amount of migalastat or a salt thereof for the purpose of stabilizing the patient's MWFS, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE). [Embodiment 58] 58. The method of embodiment 57, wherein the patient had MWFS disorder prior to initiation of administration of the migalastat or salt thereof. [Embodiment 59] 59. The method of embodiment 57 or 58, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. [Embodiment 60] 60. The method of any one of embodiments 57-59, wherein the patient is administered about 123 mg FBE of the migalastat or salt thereof every other day. [Embodiment 61] 61. The method of any one of embodiments 57-60, wherein the patient is administered about 123 mg of migalastat free base every other day. [Embodiment 62] 61. The method of any one of embodiments 57 to 60, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. [Embodiment 63] 63. The method of any one of embodiments 57-62, wherein the formulation comprises an oral dosage form. [Embodiment 64] 64. The method of embodiment 63, wherein the oral dosage form comprises a tablet, capsule, or liquid. [Embodiment 65] 65. The method according to any one of embodiments 57 to 64, wherein the migalastat or a salt thereof is administered for at least 12 months. [Embodiment 66] 66. The method according to any one of embodiments 57 to 65, wherein the migalastat or salt thereof is administered for at least 30 months. [Embodiment 67] 67. The method according to any one of embodiments 57 to 66, wherein the patient is an enzyme replacement therapy (ERT) experienced patient. [Embodiment 68] 68. The method of any one of embodiments 57 to 67, wherein administration of migalastat or a salt thereof results in a mean change in MWFS of greater than about -0.5% in a group of ERT-experienced patients with MWFS disorders after the administration of migalastat or a salt thereof for 30 months. [Embodiment 69] 69. The method of any one of embodiments 57 to 68, wherein the patient has a HEK assay-adaptive mutation in alpha-galactosidase A. [Embodiment 70] 70. The method of embodiment 69, wherein the mutation is disclosed in a pharmacological reference table. [Embodiment 71] The method of embodiment 70, wherein the pharmacological reference table is provided in the product label of a migalastat product approved for the treatment of Fabry disease. [Embodiment 72] The method of embodiment 70, wherein the pharmacological reference table is provided in the GALAFOLD® product label. [Embodiment 73] 71. The method of embodiment 70, wherein the pharmacological reference table is provided on a website. [Embodiment 74] The method of embodiment 73, wherein the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com.

Claims

1. A formulation comprising an effective amount of migalastat or a salt thereof for increasing midwall fractional shortening (MWFS) in enzyme replacement therapy (ERT) naive patients with Fabry disease, wherein the effective amount is 100 mg to 150 mg free base equivalent (FBE), and the formulation is administered to the patient every other day.

2. 2. The formulation of claim 1, wherein the patient has MWFS disorder prior to initiation of administration of migalastat or a salt thereof.

3. The formulation according to claim 1 or 2, wherein migalastat or a salt thereof enhances α-galactosidase A activity.

4. The formulation of any one of claims 1 to 3, wherein the effective amount is 123 mg FBE.

5. The formulation of any one of claims 1 to 4, wherein the effective amount is 123 mg of migalastat free base.

6. The formulation according to any one of claims 1 to 4, wherein the effective amount is 150 mg of migalastat hydrochloride.

7. The formulation of any one of claims 1 to 6, wherein the formulation comprises an oral dosage form.

8. 8. The formulation of claim 7, wherein the oral dosage form comprises a tablet, capsule, or liquid.

9. The formulation according to any one of claims 1 to 8, wherein migalastat or a salt thereof is administered for at least 12 months.

10. The formulation of any one of claims 1 to 9, wherein migalastat or a salt thereof is administered for at least 24 months.

11. 11. The formulation of any one of claims 1 to 10, wherein administration of migalastat or a salt thereof results in a mean increase in MWFS of at least about 1% in a population of ERT-naive patients with MWFS disorders after administration of migalastat or a salt thereof for 24 months.

12. The formulation of any one of claims 1 to 11, wherein the patient has a HEK assay-compatible mutation in α-galactosidase A.

13. The formulation of any one of claims 2 to 12, wherein administration of migalastat or a salt thereof normalizes the patient's MWFS.

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