Use of migalastat in reducing risk of cerebrovascular event in patients with fabry disease

Abstract

To provide methods for the treatment of Fabry disease in a patient and / or reducing the risk of a cerebrovascular (CBV) event in a patient having Fabry disease.SOLUTION: Certain methods relate to the treatment of ERT-experienced or ERT-naive Fabry patients. Certain methods comprise administering to the patient about 100 mg to about 150 mg free base equivalent of migalastat for reducing the risk of a CBV event.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 lysosomal storage disorders, and particularly to the use of migalastat for the treatment of Fabry disease. [Background technology]

[0002] Fabry disease is a progressive, X-linked congenital disorder of glycosphingolipid metabolism caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) as a result of mutations in the α-Gal A gene (GLA). Despite being an X-linked disorder, females can develop clinical symptoms to varying degrees. Fabry disease is rare, occurring in an estimated 1 in 40,000 to 1 in 117,000 males in the general population. Furthermore, there is a late-onset phenotypic variant of Fabry disease that may be underdiagnosed because it does not present with the classic signs and symptoms. This, along with newborn screening for Fabry disease, suggests that the actual incidence of Fabry disease may be higher than current estimates.

[0003] Untreated, vascular disease affects the kidneys, heart, and / or central nervous system, reducing life expectancy and usually resulting in death in the third or fourth decade of life. The 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 due to glycosphingolipid deposition usually occurs between the second and fourth decades of life, but can occur as early as the teenage years. Renal involvement is found in both hemizygous (males) and heterozygous (female) patients.

[0004] Cardiac disease occurs in most men and many women as a result of Fabry disease. Early cardiac findings include left ventricular enlargement, valvular disorders, and conduction abnormalities. Mitral valve insufficiency is the most common valvular lesion, typically presenting in childhood or adolescence. Cerebrovascular symptoms primarily result from multifocal small-vessel disease and can include thrombosis, transient ischemic attacks, basilar artery ischemia and aneurysms, stroke, hemiplegia, hemisensory loss, aphasia, labyrinthine disorders, or cerebral hemorrhage. The average age at onset of cerebrovascular symptoms is 33.8 years. Personality changes and psychotic behavior may appear with increasing age.

[0005] One approved therapy for treating Fabry disease is enzyme replacement therapy (ERT), which typically involves intravenous infusion of a purified form of the corresponding wild-type protein. Two α-Gal A preparations are currently available for the treatment of Fabry disease: agalsidase alfa (Replagal®, Shire Human Genetic Therapies) and agalsidase beta (Fabrazyme®, Sanofi Genzyme Corporation). While ERT is effective in many situations, treatment has limitations. ERT has not been proven to reduce the risk of stroke, the heart muscle responds slowly, and GL-3 excretion from some kidney cell types is limited. Some patients also develop an immune response to ERT. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there remains a need for therapies for the treatment of Fabry disease, particularly to reduce the risk of cerebrovascular events. [Means for solving the problem]

[0007] Various aspects of the invention relate to the treatment of Fabry disease in ERT-naive and ERT-experienced patients with migalastat. Such treatment can include reducing the risk of cerebrovascular (CBV) events. In various embodiments, treatment involves long-term migalastat therapy, e.g., treatment for at least 2, 3, 4 years, or more.

[0008] One aspect of the present invention relates to a method for reducing the risk of CBV events 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 free base equivalent (FBE).

[0009] In one or more embodiments, the CBV event comprises one or more of brain stem ischemia, cerebral infarction, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, embolic stroke, or transient ischemic attack.

[0010] In one or more embodiments, the patient has an increased risk of a CBV event prior to initiation of administration of migalastat or a salt thereof.

[0011] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0012] In one or more embodiments, the patient is administered about 123 mg FBE of migalastat or a salt thereof every other day.

[0013] In one or more embodiments, the patient is administered about 123 mg of migalastat free base every other day.

[0014] In one or more embodiments, the patient is administered about 150 mg of migalastat hydrochloride every other day.

[0015] In one or more embodiments, the formulation comprises an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, capsule, or solution.

[0016] In one or more embodiments, the migalastat or a salt thereof is administered for at least two years.

[0017] In one or more embodiments, the migalastat or a salt thereof is administered for at least three years.

[0018] In one or more embodiments, the migalastat or a salt thereof is administered for at least four years.

[0019] In one or more embodiments, the patient is an ERT-naive patient.

[0020] In one or more embodiments, the patient is an ERT-experienced patient.

[0021] In one or more embodiments, the patient has a HEK assay-compatible mutation in α-galactosidase A. In one or more embodiments, the mutation is disclosed in a pharmacological reference table. In one or more embodiments, a pharmacological reference table is provided on the drug product labeling of a migalastat drug product approved for the treatment of Fabry disease. In one or more embodiments, a pharmacological reference table is provided on the drug product labeling of GALAFOLD®. In one or more embodiments, a pharmacological reference table is provided on a website. In one or more embodiments, the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com.

[0022] Another aspect of the present invention relates to a method for treating Fabry disease in a patient at increased risk of a CBV event, 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.

[0023] In one or more embodiments, the CBV event comprises one or more of brain stem ischemia, cerebral infarction, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, embolic stroke, or transient ischemic attack.

[0024] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0025] In one or more embodiments, the patient is administered about 123 mg FBE of migalastat or a salt thereof every other day.

[0026] In one or more embodiments, the patient is administered about 123 mg of migalastat free base every other day.

[0027] In one or more embodiments, the patient is administered about 150 mg of migalastat hydrochloride every other day.

[0028] In one or more embodiments, the formulation comprises an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, capsule, or solution.

[0029] In one or more embodiments, the migalastat or a salt thereof is administered for at least two years.

[0030] In one or more embodiments, the migalastat or a salt thereof is administered for at least three years.

[0031] In one or more embodiments, the migalastat or a salt thereof is administered for at least four years.

[0032] In one or more embodiments, the patient is an ERT-naive patient.

[0033] In one or more embodiments, the patient is an ERT-experienced patient.

[0034] In one or more embodiments, the patient has a HEK assay-compatible mutation in α-galactosidase A. In one or more embodiments, the mutation is disclosed in a pharmacological reference table. In one or more embodiments, a pharmacological reference table is provided on the drug product labeling of a migalastat drug product approved for the treatment of Fabry disease. In one or more embodiments, a pharmacological reference table is provided on the drug product labeling of GALAFOLD®. In one or more embodiments, a pharmacological reference table is provided on a website. In one or more embodiments, the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com.

[0035] Further features of the present invention will become apparent from the following description and accompanying drawings. [Brief explanation of the drawings]

[0036] [Figures 1A-1E] The complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1) is shown. [Figure 2] The wild-type α-Gal A protein (SEQ ID NO: 2) is shown. [Figure 3] The nucleic acid sequence encoding the wild-type α-Gal A protein (SEQ ID NO:3) is shown. DETAILED DESCRIPTION OF THE INVENTION

[0037] 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.

[0038] 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 dosing regimen of migalastat results in a reduction in the risk of CBV events.

[0039] 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.

[0040] The term "Fabry disease" refers to an X-linked congenital abnormality of glycosphingolipid catabolism resulting from deficient lysosomal α-Gal A activity. This defect leads to the accumulation of the substrate globotriaosylceramide ("GL-3," also known as 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 lyso-Gb3").

[0041] The term "atypical Fabry disease" refers to patients who have primarily the cardiac manifestations of α-Gal A deficiency, i.e., progressive GL-3 accumulation in cardiomyocytes leading to significant hypertrophy of the heart (especially the left ventricle).

[0042] 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.

[0043] "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.

[0044] "Fabry 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 occur with equal prevalence in hemizygous male and female carriers, although females are typically affected with less severe disease.

[0045] 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 Figures 1A-E (SEQ ID NO: 1). 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 Figure 2 (SEQ ID NO: 2). The nucleic acid sequence containing only the coding region (i.e., exons) of SEQ ID NO: 1 is shown in Figure 3 (SEQ ID NO: 3).

[0046] 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 endoplasmic reticulum (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.

[0047] 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.

[0048] As used herein, the term "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 the 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, this term does not refer to endogenous chaperones, such as BiP, or nonspecific agents, i.e., chemical chaperones, such as glycerol, DMSO, or heavy water, which 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).

[0049] 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.

[0050] 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.

[0051] "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).

[0052] 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.

[0053] 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.

[0054] A "responder" is an individual diagnosed with or suspected of having a lysosomal storage disorder (LSD), e.g., Fabry disease, whose cells respond to contact with PC by exhibiting a sufficient increase in α-Gal A activity and / or alleviation of symptoms or enhancement of a surrogate marker, respectively. Non-limiting examples of enhanced Fabry surrogate markers include lyso-GB3 and those disclosed in U.S. Patent Application Publication No. 2010 / 0113517, which is incorporated herein by reference in its entirety.

[0055] 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 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; absence of lamellar inclusions (zebra bodies) in glomerular epithelial cells; enhanced renal function; reduced hypohidrosis; 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; and reduction of neuropathic pain, which manifests as acroparesthesia (burning or tingling pain in the extremities). Another clinical marker that may determine Fabry disease is the prevalence of adverse cardiovascular symptoms.

[0056] A dose that achieves one or more of the responses described above is a "therapeutically effective dose."

[0057] 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 Pharmacopoeia 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. Preferred carriers include water or aqueous solutions, saline solutions, and aqueous dextrose and glycerol solutions, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 18th Edition, or other editions.

[0058] 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.

[0059] The term "enzyme replacement therapy" or "ERT" refers to the introduction of a purified, non-naturally occurring enzyme into an individual having a deficiency of such enzyme. The administered protein can be obtained from natural sources or by recombinant expression (as described in more detail below). The term also refers to the introduction of a purified enzyme into an individual who otherwise requires or would benefit from administration of the purified enzyme (e.g., an individual suffering from an enzyme deficiency). The introduced enzyme can be a purified recombinant enzyme produced in vitro, or a protein purified from isolated tissue or fluid, such as from placenta or animal milk or a plant.

[0060] The term "ERT-naive patient" refers to a Fabry patient who has never received ERT or has not received ERT for at least 6 months prior to initiating migalastat therapy.

[0061] The term "ERT-experienced patient" refers to a Fabry patient 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.

[0062] As used herein, the term "free base equivalent" or "FBE" refers to the amount of migalastat present in migalastat or its salts. 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, based on the weight of the hydrochloride salt, 150 mg of migalastat hydrochloride provides only 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.

[0063] The term "migalastat" includes migalastat free base or a pharmaceutically acceptable salt thereof (eg, migalastat HCl), unless specifically specified to the contrary.

[0064] The terms "mutation" and "mutation" (e.g., as in "applicable mutation or mutation") refer to a change in the nucleotide sequence of a gene or chromosome. The two terms referenced herein are typically used collectively, e.g., as in "mutation or mutation," and refer to the change in nucleotide sequence specified in the preceding sentence. If for any reason only one of the two terms is listed, the missing term is intended to be included and should be understood as such. Furthermore, the terms "applicable mutation" and "applicable mutation" refer to a mutation or mutation applicable to PC therapy, e.g., a mutation applicable to migalastat therapy. A particular type of applicable mutation or mutation is a "HEK assay-applicable mutation or mutation," which is a mutation or mutation determined to be applicable to migalastat therapy according to the criteria of the in vitro HEK assay described herein and in U.S. Pat. No. 8,592,362, the entire contents of which are incorporated herein by reference.

[0065] 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.

[0066] Fabry disease Fabry disease is a rare, progressive, severe, X-linked LSD. 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.

[0067] 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 associated with males who have 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 associated with males who have 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.

[0068] Over 1,000 GLA mutations that cause Fabry disease have been identified. Approximately 60% are missense mutations that result 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 ER prevent these abnormal proteins from trafficking to lysosomes, targeting them for early degradation and removal. Many missense mutant forms are targets of migalastat, an α-Gal A-specific pharmacological chaperone.

[0069] The clinical symptoms of Fabry disease range in severity and correlate roughly with the patient's residual α-Gal A levels. The majority of currently treated patients are referred to as classic Fabry patients, most of whom are men. These patients experience disease in various organs, including the kidneys, heart, and brain. Disease symptoms first appear during adolescence and typically progress in severity until death in the third or fourth decade of life. 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 A levels than classic Fabry patients. Late-onset Fabry patients typically experience their first disease symptoms in adulthood and often have disease symptoms focused on 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.

[0070] Patients with Fabry disease have progressive renal dysfunction, and untreated individuals develop end-stage renal failure by their fourth decade. Deficiency of α-Gal A activity leads to the accumulation of GL-3 and related glycosphingolipids in many cell types, including those of the kidney. GL-3 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.

[0071] 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.

[0072] In one or more embodiments, a mutant form of α-Gal 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-Gal A is expressed in HEK-293 cells according to a Good Laboratory Practice (GLP)-validated in vitro assay (the GLP HEK or migalastat applicability assay) (referred to as the "HEK assay"). Such mutations are also referred to herein as "HEK assay-applicable" mutations.

[0073] Prior screening methods have been proposed 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.

[0074] 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.

[0075] 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-3,4,5triol, is a compound having the following chemical formula: TIFF2025128105000001.tif49170

[0076] 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 will be adjusted so that the dose of migalastat taken by the patient is equivalent to the amount that would have been taken if migalastat free base had been used. An example of a pharmaceutically acceptable salt of migalastat is migalastat HCl. TIFF2025128105000002.tif47170

[0077] 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 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 mutations are associated with the classic phenotype of the disease.

[0078] HEK assay applicable mutations include at least those mutations listed in a pharmacological reference table (e.g., those listed in the U.S. or international drug product label for a migalastat drug product, such as GALAFOLD®). As used herein, a "pharmacological reference table" refers to any publicly accessible written or electronic record, either contained on the drug product label within the packaging of a migalastat drug product (e.g., GALAFOLD®) or on a website accessible by a healthcare provider, that conveys whether a particular mutation or variant will respond to migalastat (e.g., GALAFOLD®) PC therapy, and is not necessarily limited to written records presented in tabular format. Thus, in one embodiment of the present invention, a "pharmacological reference table" refers to any repository of information containing one or more applicable mutations or variants. Exemplary pharmacological reference tables for HEK assay applicable mutations can be found in the GALAFOLD® Summary of Formulation Properties and / or Prescribing Information for the various countries in which GALAFOLD® is approved for use, or on websites such as www.galafoldamenabilitytable.com and www.fabrygenevariantsearch.com (each of which is hereby incorporated by reference in its entirety).

[0079] An exemplary pharmacological reference table for HEK assay-eligible mutations is provided below in Table 1. 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 one of the individual mutations in Table 1 is present.

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[0081] TIFF2025128105000004.tif230170

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[0088] TIFF2025128105000011.tif74170

[0089] Dosage, Formulation and Administration Thus, in one or more embodiments, a Fabry patient is administered migalastat or a salt thereof once every other day (also referred to as "QOD"). In various embodiments, the doses described herein relate to migalastat hydrochloride or an equivalent dose of migalastat or a salt 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."

[0090] An effective amount of migalastat or a salt thereof can 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.

[0091] 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.

[0092] In various embodiments, the 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, or about 183 mg of migalastat hydrochloride.

[0093] Thus, in various embodiments, migalastat therapy comprises administering 150 mg of migalastat hydrochloride every other day, such as 123 mg FBE once every other day.

[0094] Administration of migalastat or a salt thereof can be over a period of time. In one or more embodiments, migalastat or a salt thereof is administered for a duration of 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 about 2, 3, 4, or 5 years.

[0095] The administration of migalastat or a salt thereof according to 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. As an example, a patient is orally administered capsules each containing 150 mg of migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof other than hydrochloride.

[0096] 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.

[0097] In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered as monotherapy and may be in a form suitable for any route of administration, e.g., orally in tablet or capsule or liquid form, in sterile aqueous solution for injection, etc. In other embodiments, the PC is provided as a lyophilized powder that is added to the replacement enzyme formulation during or immediately after reconstitution to prevent enzyme aggregation in vitro prior to administration.

[0098] When a PC (e.g., migastat or a salt thereof) 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 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). 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.

[0099] Pharmaceutical formulations of PC (e.g., migastat or its salts) 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 dispersions. 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 (e.g., 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.

[0100] Sterile injectable solutions are prepared by blending the required amount of purified enzyme (if present) and PC (e.g., migalastat or its salts) in an appropriate solvent with various other ingredients as listed 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 listed 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.

[0101] 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, and bicarbonate buffer, amino acids, urea, alcohols, ascorbic acid, 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.

[0102] 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.

[0103] 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.

[0104] Embodiments relating to pharmaceutical formulations and administration may 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 reducing the risk of a CBV event, methods of treating Fabry patients at increased risk of a CBV event, methods of treating Fabry patients with a history of CBV events, methods of treating Fabry patients without a history of CBV events, methods of enhancing α-Gal A in patients diagnosed with or suspected of having Fabry disease, embodiments relating to the use of a pharmacological chaperone to α-Gal A for the manufacture of a medicament for treating patients diagnosed with Fabry disease, or embodiments relating to a pharmacological chaperone to α-Gal A for use in treating patients diagnosed with Fabry disease, as well as embodiments relating to applicable mutations, PCs and suitable dosages thereof.

[0105] In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered in combination with ERT. ERT increases the amount of protein by exogenously introducing a wild-type or biologically functional enzyme via infusion. This therapy has been developed for many genetic disorders, including LSDs such as Fabry disease, as described above. After infusion, the exogenous enzyme is assumed 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, subject to rapid intracellular degradation, and there is also the possibility of adverse immune reactions with subsequent treatment. In one or more embodiments, a chaperone is administered simultaneously with the replacement enzyme (e.g., replacement α-Gal A). In some embodiments, the chaperone is formulated with the replacement enzyme (e.g., replacement α-Gal A).

[0106] In one or more embodiments, the patient is switched from ERT to migalastat therapy.In some embodiments, the patient who is receiving ERT is identified, the patient's ERT is discontinued, and the patient begins to receive migalastat therapy.The migalastat therapy can be according to any of the methods described herein.

[0107] CBV events The dosing regimen described herein can reduce the risk of CBV events in Fabry patients. CBV events, including but not limited to stroke and transient ischemic attack, are common serious clinical events among Fabry disease patients, occurring in approximately 18% of untreated patients over a mean follow-up of 4.5 years, according to a meta-analysis by El Dib, et al. (El Dib R. PLoS One. 2017;12(3):e0173358). The incidence of CBV events in patients receiving ERT has been reported to range from 2% to 27%. However, the impact of ERT on the risk of CBV events remains unknown due to a lack of placebo-controlled trials, and recombinant lysosomal enzymes have not been shown to cross the blood-brain barrier.

[0108] As described in more detail in the Examples below, migalastat therapy was found in Phase 2 and Phase 3 trials to reduce the incidence of CBV events in both ERT-experienced and ERT-naive patients. Therefore, migalastat therapy can be used to reduce the risk of CBV events and / or to treat Fabry patients at high risk for CBV events, including patients with or without a history of CBV events. [Example]

[0109] Example 1: Dosing regimens for the treatment of ERT-experienced and ERT-naive Fabry patients with migalastat hydrochloride This example describes a phase 2 and 3 trial of migalastat therapy in ERT-experienced and ERT-naive Fabry patients.

[0110] Test Design This analysis included data from four Phase 2 and four Phase 3 clinical trials with a data cutoff of February 10, 2017, as shown in Figure X1 below.

[0111] FAB-CL-202 (NCT00283959), FAB-CL-203 (NCT00283933), and FAB-CL-204 (NCT00304512) were phase 2, open-label, non-comparative studies evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of migalastat (dose range: 50–250 mg) in patients with Fabry disease.

[0112] FAB-CL-205 (NCT0052607) was a Phase 2 long-term open-label extension (OLE) study in patients who completed Phase 2 clinical trials, including FAB-CL-202, FAB-CL-203, and FAB-CL-204. The study included migalastat 150 mg every other day (QOD), followed by a dose-escalation period, followed by a period of 150 mg QOD.

[0113] FACETS (AT1001-011, NCT00925301) was a phase 3, placebo-controlled trial designed to evaluate the efficacy, safety, and PD of 6 months of migalastat 150 mg QOD versus placebo, followed by an 18-month open-label extension (OLE) of migalastat, in ERT-naive patients with Fabry disease and migalastat-eligible GLA mutations.

[0114] ATTRACT (AT1001-012, NCT01218659) was a phase 3, open-label, active-controlled trial to compare the efficacy and safety of 18 months of migalastat 150 mg QOD versus ERT followed by 12 months of migalastat OLE in ERT-treated patients with migalastat-eligible GLA mutations.

[0115] AT1001-041 (NCT01458119) was a long-term OLE study evaluating the long-term safety and efficacy of migalastat in patients who completed FAB-CL-205, AT1001-011, or AT1001-012.

[0116] AT1001-042 (NCT02194985) is an extension long-term OLE study evaluating the long-term safety and efficacy of migalastat in patients who participated in AT1001-012 or AT1001-041.

[0117] analysis The analysis will evaluate CBV events reported as treatment-emergent adverse events (TEAEs) during migalastat 150 mg QOD treatment in patients with applicable mutations in phase 2 and 3 clinical trials.

[0118] CBV events were identified by searching medical history and TEAE lists using stroke-related terms, including brainstem ischemia, cerebral infarction, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, embolic stroke, and TIA.

[0119] Only eligible patients who received at least one dose of migalastat 150 mg QOD were included in this analysis.

[0120] Applicability was based on a Good Laboratory Practice (GLP) validated in vitro migalastat applicability assay.

[0121] Clinical trials included in the analysis TIFF2025128105000012.tif206170

[0122] result Migalastat 150mg QOD total exposure The total mean (SD) duration of exposure to migalastat 150 mg QOD was 4.0 (2.0) years (N=114).

[0123] Duration of exposure to migalastat 150 mg QOD ranged from 0.1 to 8.3 years, with a median of 4.4 years.

[0124] Demographics and baseline characteristics The mean (SD) age of all eligible patients receiving at least one dose of migalastat 150 mg QOD was 46.2 (13.1) years (range: 16-72 years) (Table 2). The majority were white, and 57.0% were female. The mean (SD) time since diagnosis of Fabry disease was 9.8 (10.1) years (range: 1-44 years).

[0125] TIFF2025128105000013.tif173170

[0126] History of CBV events Sixteen of 114 patients (14%) experienced a CBV event before migalastat treatment (Table 3). One patient from study AT1001-012 reported two CBV events in his medical history.

[0127] In 5 / 16 patients, CBV events were considered as current conditions reported in the medical history at study entry. One patient from AT1001-011 had ongoing cerebral ischemia, and one had ongoing brainstem infarction. Two patients from AT1001-012 had ongoing TIA, and one had ongoing cerebrovascular accident, specifically left middle cerebral artery stroke.

[0128] The mean (SD) age at the time of the first CBV event was 43.6 (14.4) years.

[0129] TIFF2025128105000014.tif168170

[0130] Occurrence of CBV events during migalastat 150mg QOD treatment Eleven CBV events were reported in eight patients (7%) during treatment with migalastat 150 mg QOD (Table 4). Seven CBV events were categorized as serious adverse events (SAEs), but most (82%) events were mild to moderate in severity (Table 5). Two CBV events led to treatment discontinuation (Table 5). None of the 11 CBV events were considered treatment-related.

[0131] Six of eight patients experienced CBV before receiving migalastat treatment, so only 2 / 114 (2%) patients had their first CBV event while receiving migalastat (Table 5). The mean (SD) age of patients with a first event during migalastat treatment was 50.6 (14.6) years (Table 5). The mean (SD) duration of migalastat 150 mg QOD administration at the time of the first event was 1.1 (1.1) years.

[0132] Of the 16 patients with premigralstat CBV events, 10 (63%) experienced no new CBV events during premigralstat treatment.

[0133] TIFF2025128105000015.tif158170

[0134] TIFF2025128105000016.tif191170

[0135] As can be seen from the table above, the overall incidence of CBV events was low during migalastat treatment. During a mean of 4 years on migalastat, 8 / 114 (7%) patients experienced a CBV event, primarily in patients with a history of CBV events.

[0136] The embodiments described herein are intended to exemplify the compositions and methods, and are not intended to limit the scope of the present invention. Various modifications and variations that are consistent with the description as a whole and that are easily apparent to those skilled in the art are intended to be included. The scope of the appended claims should not be limited by the specific embodiments shown in the examples, but should be accorded the broadest interpretation consistent with the description as a whole.

[0137] Patents, patent applications, publications, formulation descriptions, GenBank accession numbers, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entireties for all purposes.

Claims

1. 1. A method for reducing the risk of a cerebrovascular (CBV) event in a patient with Fabry disease, comprising administering to the patient every other day for at least two years a formulation comprising 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).

2. 10. The method of claim 1, wherein the CBV event comprises one or more of brainstem ischemia, cerebral infarction, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, embolic stroke, or transient ischemic attack.

3. 3. The method of claim 1 or 2, wherein the patient has an increased risk of a CBV event prior to initiation of administration of migalastat or a salt thereof.

4. The method according to any one of claims 1 to 3, wherein the migalastat or a salt thereof enhances α-galactosidase A activity.

5. 5. The method of any one of claims 1 to 4, wherein the patient is administered about 123 mg FBE of migalastat or a salt thereof every other day.

6. 6. The method of any one of claims 1 to 5, wherein the patient is administered about 123 mg of migalastat free base every other day.

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

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

9. 10. The method of claim 8, wherein the oral dosage form comprises a tablet, capsule, or solution.

10. The method of any one of claims 1 to 9, wherein the migalastat or a salt thereof is administered for at least 3 years.

11. The method of any one of claims 1 to 10, wherein the migalastat or a salt thereof is administered for at least four years.

12. The method of any one of claims 1 to 11, wherein the patient has not had a first CBV event before starting administration of the migalastat or salt thereof.

13. The method of any one of claims 1 to 11, wherein the patient had a first CBV event before initiating administration of the migalastat or salt thereof.

14. The method of any one of claims 1 to 13, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

15. The method of any one of claims 1 to 13, wherein the patient is an ERT-experienced patient.

16. The method of any one of claims 1 to 15, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A.

17. 17. The method of claim 16, wherein the mutation is disclosed in a pharmacological reference table.

18. 18. The method of claim 17, wherein the pharmacological reference table is provided on the drug product label of a migalastat drug product approved for the treatment of Fabry disease.

19. 19. The method of claim 18, wherein the pharmacological reference table is provided on the drug product label of GALAFOLD®.

20. 20. The method of claim 18, wherein the pharmacological reference table is provided on a website.

21. 21. The method of claim 20, wherein the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com.

22. 1. A method of treating Fabry disease in a patient at increased risk of a cerebrovascular (CBV) event, comprising administering to the patient every other day for at least two years a formulation comprising 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).

23. 23. The method of claim 22, wherein the CBV event comprises one or more of brainstem ischemia, cerebral infarction, cerebral hemorrhage, cerebral ischemia, cerebrovascular accident, embolic stroke, or transient ischemic attack.

24. The method according to claim 21 or 22, wherein the migalastat or a salt thereof enhances α-galactosidase A activity.

25. 25. The method of any one of claims 22 to 24, wherein the patient is administered about 123 mg FBE of the migalastat or salt thereof every other day.

26. 26. The method of any one of claims 22-25, wherein the patient is administered about 123 mg of migalastat free base every other day.

27. 26. The method of any one of claims 22 to 25, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day.

28. The method of any one of claims 22 to 27, wherein the formulation comprises an oral dosage form.

29. 29. The method of claim 28, wherein the oral dosage form comprises a tablet, capsule, or solution.

30. 30. The method of any one of claims 22 to 29, wherein the migalastat or a salt thereof is administered for at least 3 years.

31. The method of any one of claims 22 to 30, wherein the migalastat or a salt thereof is administered for at least four years.

32. The method of any one of claims 22 to 31, wherein the patient has not had a first CBV event before initiating administration of the migalastat or salt thereof.

33. The method of any one of claims 22 to 31, wherein the patient had a first CBV event before initiating administration of the migalastat or salt thereof.

34. The method of any one of claims 22 to 33, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

35. The method of any one of claims 22 to 33, wherein the patient is an ERT-experienced patient.

36. The method of any one of claims 22 to 35, wherein the patient has a HEK assay-applicable mutation in α-galactosidase A.

37. 37. The method of claim 36, wherein the mutation is disclosed in a pharmacological reference table.

38. 38. The method of claim 37, wherein the pharmacological reference table is provided in the drug product label of a migalastat drug product approved for the treatment of Fabry disease.

39. 39. The method of claim 38, wherein the pharmacological reference table is provided on the formulation label of GALAFOLD®.

40. 39. The method of claim 38, wherein the pharmacological reference table is provided on a website.

41. 41. The method of claim 40, wherein the website is one or more of www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com.

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