Methods of improving the pharmacokinetics of migalastat

Abstract

A method to improve the pharmacokinetics of migalastat by restricting caffeine intake during migalastat therapy is provided.

Description

Technology Field

[0001] The principles and embodiments of the present invention generally relate to a method for improving the pharmacokinetics of migalastat. Background Technology

[0003] Many human diseases originate from mutations that cause changes in the amino acid sequences of proteins, which can reduce protein stability and prevent proper folding. Proteins generally fold in specific regions of the cell known as the endoplasmic reticulum or ER. Cells possess quality control mechanisms to ensure that proteins fold into the correct three-dimensional shape before moving from the ER to their appropriate intracellular destinations; this process is commonly referred to as protein trafficking. Misfolded proteins are initially retained in the ER and are often removed by these quality control mechanisms. In certain cases, misfolded proteins can accumulate in the ER before being removed. The retention of misfolded proteins in the ER interferes with proper trafficking, and the resulting reduced biological activity can lead to impaired cellular function and ultimately disease. Furthermore, the accumulation of misfolded proteins in the ER can induce various types of stress on the cell, which can also contribute to cellular dysfunction and disease.

[0004] These mutations can cause lysosomal storage disorders (LSDs), characterized by a deficiency of lysosomal enzymes resulting from mutations in the genes encoding these enzymes. The resulting disease leads to the pathological accumulation of substrates for these enzymes, including lipids, carbohydrates, and polysaccharides. While there are many different mutant genotypes associated with each LSD, many of the mutations are missense mutations that can lead to the production of less stable enzymes. These less stable enzymes are sometimes degraded prematurely by the ER-associated degradation pathway. This results in lysosome enzyme deficiency and the pathological accumulation of substrates. These mutant enzymes are sometimes referred to in the relevant technical field as "folding mutants" or "stereomorphic mutants."

[0005] Fabry disease, an LSD, is a progressive X-linked congenital error in glycosphingolipid metabolism caused by a deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) due to a mutation in the α-Gal A gene (GLA). Despite being an X-linked disorder, women may present with varying degrees of clinical manifestations.

[0006] Fabry disease is classified into three groups based on clinical findings: the classic form with systemic vascular disease, the atypical variant with clinical findings limited to cardiac tissue, and late-onset disease including female carriers with mild to severe forms of the disease. Clinical findings include angiokeratosis (small, raised reddish-purple lesions on the skin), paresthesia (burning sensation in the hands and feet), hypohidrosis (reduced ability to sweat), and characteristic corneal and lens opacity ( The Metabolic and Molecular Bases of Inherited Disease , 8th Edition 2001, Scriver et al., ed., pp. 3733-3774, McGraw-Hill, New York).

[0007] Fabry disease is a rare disease, with an estimated incidence of 1 in 40,000 men to 1 in 117,000 people in the general population. Furthermore, there is a late-onset variant of Fabry disease that may be underdiagnosed because it does not exhibit classic signs and symptoms. This, along with newborn screening for Fabry disease, suggests that the actual incidence of Fabry disease may be higher than currently estimated.

[0008] The life expectancy of untreated Fabry patients is reduced, and they typically die in their 40s or 50s due to vascular disease affecting the kidneys, heart, and / or central nervous system. Enzyme deficiency causes the intracellular accumulation of the substrate globotriaosylceramide (GL-3) in vascular endothelium and visceral tissues throughout the body. Additionally, the heart may become hypertrophic, and the kidneys may be progressively affected. The progressive deterioration of renal function and the development of azotemia due to glycosphingolipid deposition typically occur between the ages of 30 and 50, but can occur as early as the 20s. Renal lesions are found in both hemizygous (male) and heterozygous (female) patients. Affected men have reduced life expectancy and typically die in their 40s or 50s due to vascular disease of the heart, brain, and / or kidneys. Other symptoms include fever, particularly after meals, and gastrointestinal disturbances.

[0009] Cardiac disease caused by Fabry disease occurs in most men and many women. Early cardiac findings include left ventricular hypertrophy, valvular involvement, and conduction abnormalities. Mitral insufficiency is the most frequent valvular lesion, typically present during childhood or adolescence. Cerebrovascular findings originate primarily from multifocal microvessel involvement and may include thrombosis, transient ischemic attack, basilar artery ischemia and aneurysms, seizures, hemiparesis, unilateral sensory loss, aphasia, labyrinthine disorders, or cerebral hemorrhage. The average age of onset for cerebrovascular findings is 33.8 years. Personality changes and psychotic behaviors may appear with age.

[0010] Individuals with late-onset Fabry disease can be male or female. Late-onset Fabry disease manifests as atypical variants, and there is growing evidence that there may be a significant number of unexplained "atypical variants" worldwide. Women who inherit an X chromosome containing the α-GAL mutation may develop symptoms later, significantly increasing the prevalence of the disease. These patients typically experience disease symptoms for the first time in adulthood and often have symptoms concentrated in a single organ. For example, many men and women with late-onset Fabry disease have left ventricular hypertrophy. Late-onset Fabry disease can also manifest as stroke of unknown etiology. As patients age, cardiac complications of the disease can progress and lead to death.

[0011] Patients with the mild "cardiac variant" of Fabry disease generally have 5–15% normal α-GAL activity and exhibit left ventricular hypertrophy or cardiomyopathy. These patients with the cardiac variant remain essentially asymptomatic when the classically affected counterparts are severely damaged. The cardiac variant was found in 11% of adult male patients with unexplained left ventricular hypertrophic cardiomyopathy, suggesting that Fabry disease may be more frequent than previously estimated ( Nakao et al. , N. Engl. J. Med. 1995; 333: 288-293).

[0012] There have been various approaches to the treatment of Fabry disease. One approved therapy for treating Fabry disease is enzyme replacement therapy (ERT), which typically involves the intravenous infusion of a purified form of the corresponding wild-type protein (Fabrazyme®, Genzyme Corp.). However, ERT has several drawbacks. One of the major complications of enzyme replacement therapy is the rapid degradation of the infused protein, which necessitates numerous costly high-dose infusions. ERT is subject to several additional precautions, such as the difficulty of large-scale production, purification, and storage of properly folded proteins; the acquisition of glycosylated natural proteins; the generation of anti-protein immune responses; and the inability of the protein to cross the blood-brain barrier to mitigate central nervous system pathology (i.e., low bioavailability). Furthermore, the replacement enzyme cannot penetrate the heart or kidney in sufficient quantities to reduce substrate accumulation in renal podocytes or cardiac myocytes, which is prominent in Fabry pathology.

[0013] Additionally, ERT typically involves the intravenous infusion of a purified form of the corresponding wild-type protein. Currently, two α-Gal A products are available for the treatment of Fabry disease: agalsidase alpha (Replagal®, Shire Human Genetic Therapies) and agalsidase beta (Fabrazyme®; Sanofi Genzyme Corporation). While ERT is effective in many settings, there are limitations to its treatment. ERT has not been proven to reduce the risk of stroke, cardiac muscle responds slowly, and the clearance of GL-3 from some renal cell types is limited. Some patients also exhibit an immune response to ERT.

[0014] Another approach to treating certain enzyme deficiencies involves using small molecule inhibitors to reduce the production of natural substrates for the deficient enzyme proteins, thereby improving the pathology. This "substrate reduction" approach has been specifically described for about 40 related classes of enzyme disorders known as lysosomal storage disorders, including glycosphingolipid storage disorders. Small molecule inhibitors proposed for therapeutic use are specific to inhibiting enzymes involved in glycolipid synthesis and reduce the amount of cellular glycolipids that must be degraded by the deficient enzyme.

[0015] A third approach to the treatment of Fabry disease is treatment with so-called pharmacological chaperones (PCs). These PCs include small molecule inhibitors of α-Gal A, which bind to α-Gal A and can increase the stability of both the mutant enzyme and the corresponding wild type. One of these PCs for α-Gal A is migalastat.

[0016] Therefore, there remains a need for a therapy to treat Fabry disease.

[0018] summation

[0019] Various aspects of the present invention relate to a method for improving the pharmacokinetics of migalastat.

[0020] One aspect of the present invention relates to a method for administering migalastat to a patient, the method comprising orally administering to a patient a formulation comprising a therapeutically effective dose of migalastat or a salt thereof, wherein the patient does not consume caffeine within a specific time interval after administering the formulation comprising migalastat or a salt thereof. In various embodiments, this time interval comprises refraining from caffeine for at least 30 minutes, at least 60 minutes (1 hour), at least 90 minutes (1.5 hours), at least 2 hours, at least 2.5 hours, at least 3 hours, or at least 4 hours before administering migalastat or a salt thereof, and for at least 30 minutes, at least 60 minutes (1 hour), at least 90 minutes (1.5 hours), at least 2 hours, at least 2.5 hours, at least 3 hours, or at least 4 hours after administering migalastat or a salt thereof.

[0021] In some embodiments, the patient does not consume caffeine within a time interval between at least one hour before administering migalastat or its salt and at least one hour after administration, that is, the patient does not consume caffeine within about one hour of administering a formulation containing migalastat or its salt.

[0022] In some embodiments, the patient does not consume caffeine within a time interval between at least 2 hours before administering migalastat or its salt and at least 1 hour after administration.

[0023] In some embodiments, the patient does not consume caffeine within a time interval between at least 2 hours before administering migalastat or its salt and at least 2 hours after administration, that is, the patient does not consume caffeine within about 2 hours of administering a formulation containing migalastat or its salt.

[0024] In some embodiments, the patient does not consume caffeine within a time interval between at least 3 hours before administering migalastat or its salt and at least 2 hours after administration.

[0025] In some embodiments, the patient does not consume caffeine within a time interval between at least 3 hours before administering migalastat or its salt and at least 3 hours after administration, that is, the patient does not consume caffeine within about 3 hours of administering a formulation containing migalastat or its salt.

[0026] In some embodiments, the patient consumes caffeine outside of the caffeine abstaining time interval. For example, if the caffeine abstaining time interval is at least 2 hours before administration of migalastat or its salt and at least 2 hours after administration, in some embodiments, the patient consumes caffeine at least 2 hours before administration of migalastat or its salt and / or at least 2 hours after administration. In various embodiments, the patient consumes caffeine at least 30 minutes, at least 60 minutes (1 hour), at least 90 minutes (1.5 hours), at least 2 hours, at least 2.5 hours, at least 3 hours, or at least 4 hours before administration of migalastat or its salt. In various embodiments, the patient consumes caffeine at least 30 minutes, at least 60 minutes (1 hour), at least 90 minutes (1.5 hours), at least 2 hours, at least 2.5 hours, at least 3 hours, or at least 4 hours after administration of migalastat or its salt.

[0027] In some embodiments, not consuming caffeine within a specific time interval following the administration of a formulation containing migalastat or a salt thereof improves the pharmacokinetics of migalastat, e.g., the area under the migalastat curve (AUC) and / or the maximum plasma concentration (C max It provides avoidance of a reduction in ). In some embodiments, the patient receives AUC and C for migalastat. maxTo avoid a reduction of approximately 57% and 60%, respectively, do not consume caffeine within 2 hours of administering a formulation containing migalastat or its salt.

[0028] In some embodiments, the patient fasts during the time interval of refraining from caffeine. In some embodiments, the patient does not consume food for at least 2 hours before administering migalastat or its salt and for at least 2 hours after administration, and the patient does not consume caffeine for at least 2 hours before administering migalastat or its salt and for at least 2 hours after administration.

[0029] In some embodiments, the patient fasts for a different time interval from the time interval during which caffeine is abstained.

[0030] In some embodiments, the therapeutically effective dose of migalastat or its salt is in the range of about 100 mg to about 150 mg every other day.

[0031] In some embodiments, the therapeutically effective dose of migalastat or its salt is about 123 mg of free base equivalent (FBE) every other day.

[0032] In some embodiments, the therapeutically effective dose of migalastat or its salt is about 150 mg of migalastat hydrochloride every other day.

[0033] In one or more embodiments, the formulation includes an oral administration form. In some embodiments, the oral administration form includes a tablet, a capsule, or a solution.

[0034] Another aspect of the present invention relates to a method for treating Fabry disease in a human patient requiring treatment for Fabry disease, said method comprising orally administering to the patient a formulation comprising a therapeutically effective dose of migalastat or a salt thereof, wherein the patient does not consume caffeine within a specific time interval after administering the formulation comprising migalastat or a salt thereof. This treatment method may have any of the features described herein with respect to the method of administering migalastat.

[0035] In one or more embodiments, the patient has an HEK test-compliant mutation of α-galactosidase A. In one or more embodiments, the mutation is disclosed in a pharmacological reference table. In one or more embodiments, the pharmacological reference table is provided on the product label for a migalastat product approved for the treatment of Fabry disease. In one or more embodiments, the pharmacological reference table is provided on the product label for GALAFOLD®. In one or more embodiments, the 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. Brief explanation of the drawing

[0037] Further features of the present invention will become apparent from the description below and the accompanying drawings: Figures 1A-E show the whole DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1); Figure 2 shows the wild-type α-Gal A protein (sequence identification number: 2); Figure 3 shows the nucleic acid sequence encoding the wild-type α-Gal A protein (sequence identification number: 3); Figure 4 shows a schematic diagram of a study investigating the effects of caffeine and sweeteners on the pharmacokinetics of migalastat; Figure 5 shows the concentration-time profile of migalastat when administered with caffeine and various sweeteners. Specific details for implementing the invention

[0038] details

[0039] Before describing various exemplary embodiments of the present invention, it should be understood that the present invention is not limited to the details of the construction or process steps presented in the following description. Other embodiments of the present invention are possible and can be implemented or carried out in various ways.

[0040] Various aspects of the present invention relate to the administration of migalastat, such as in the treatment of Fabry disease. It has been surprisingly discovered that co-administration of migalastat and caffeine has a negative effect on the pharmacokinetics of migalastat, independently of the dietary effect on the pharmacokinetics of migalastat. Accordingly, various embodiments of the present invention relate to the administration of migalastat or its salt without co-administration of caffeine, that is, the patient not consuming caffeine within a specific time interval in which migalastat or its salt is administered.

[0041] definition

[0042] The terms used in this specification generally have their ordinary meanings in the relevant technical field within the context of the invention and in the specific context in which each term is used. Specific terms are discussed below or elsewhere in the specification to provide additional guidance to practitioners in describing the compositions and methods of the invention and how to make and use them.

[0043] As used herein, the phrase “the patient does not consume caffeine” and similar language refer to the patient not consuming (e.g., not eating or drinking) food, beverage, or other products containing caffeine. In some embodiments, food, beverage, or product is considered caffeine-containing if it contains a specific amount of caffeine, such as more than 1 mg, 2 mg, 5 mg, or 10 mg of caffeine. In some embodiments, examples of caffeine-containing beverages include coffee, espresso, tea, caffeine-containing energy drinks, and caffeine-containing sodas.

[0044] The term "Fabry disease" refers to an X-linked congenital error in glycosphingolipid catabolism caused by deficient lysosomal α-Gal A activity. This defect causes the accumulation of the substrate globotriaosylceramide (also known as "GL-3," Gb3, or ceramide trihexoside) and related glycosphingolipids in the vascular endothelial lysosomes of the heart, kidneys, skin, and other tissues. Another substrate of the enzyme is plasma globotriaosylsphingosine ("plasma lyso-Gb3").

[0045] The term "atypical Fabry disease" refers to patients with cardiac findings of α-Gal A deficiency, namely progressive GL-3 accumulation in myocardial cells causing significant hypertrophy of the heart, particularly the left ventricle.

[0046] A "carrier" is a female who has one X chromosome with the defective α-Gal A gene and one X chromosome with the normal gene, and has X chromosomal inactivation of the normal allele in one or more cell types. Carriers are often diagnosed with Fabry disease.

[0047] "Patient" refers to an entity diagnosed with a specific disease or suspected of having it. The patient may be a human or an animal.

[0048] "Fabry patient" refers to an individual diagnosed with Fabry disease or suspected of having it who possesses the mutated α-Gal A as additionally defined below. Characteristic markers of Fabry disease may occur with the same prevalence in male hemizygotes and female carriers, but women are typically less severely affected.

[0049] 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 access number X14448.1 and is shown in Figs. 1A-E (Sequence Identification Number: 1). The human α-Gal A enzyme consists of 429 amino acids, is available at GenBank access numbers X14448.1 and U78027.1, and is shown in Fig. 2 (Sequence Identification Number: 2). A nucleic acid sequence containing only the coding region (i.e., exon) of Sequence Identification Number: 1 is shown in Fig. 3 (Sequence Identification Number: 3).

[0050] The term "mutant protein" includes proteins that have mutations in the genes encoding the protein, which prevent the protein from achieving a stable conformation under conditions typically present in the endoplasmic reticulum (ER). Failure to achieve a stable conformation results in significant amounts of the enzyme being degraded rather than being transported to the lysosome. These mutations are sometimes referred to as "conformal mutants." Such mutations include, but are not limited to, missense mutations and inframe small deletions and insertions.

[0051] In one embodiment, the term “mutant α-Gal A” as used herein comprises α-Gal A having a mutation in the gene encoding α-Gal A that prevents the enzyme from achieving a stable conformation under conditions typically present in the ER. If a stable conformation is not achieved, a significant amount of the enzyme is degraded rather than being transported to the lysosome.

[0052] The terms “pharmacological chaperone” (“PC”) or “specific pharmacological chaperone” (“SPC”) as used herein refer 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) enhancing the formation of a stable molecular conformation of a protein; (ii) inducing the trafficking of the protein from the ER to another cellular location, preferably a natural cellular location, i.e., preventing ER-associated degradation of the protein; (iii) preventing the aggregation of misfolded proteins; and / or (iv) restoring or enhancing at least partial wild-type function and / or activity of the protein. For example, a compound that specifically binds to α-Gal A means that it binds to the enzyme and exerts a chaperone effect, rather than a general enzyme group, whether related or unrelated. More specifically, this term does not refer to endogenous chaperones, e.g., BiP, or nonspecific agents that exhibit nonspecific chaperone activity against various proteins, e.g., glycerol, DMSO, or deuterium water, i.e., chemical chaperones. In one or more embodiments of the present invention, PC may be a reversible competitive inhibitor. In one embodiment, PC is migalastat or a salt thereof. In another embodiment, PC is migalastat free base (e.g., 123 mg of migalastat free base). In yet another embodiment, PC is a salt of migalastat (e.g., 150 mg of migalastat HCl).

[0053] An enzyme's "competitive inhibitor" can refer to a compound that binds to the enzyme at nearly the same location as the substrate and is structurally similar to the enzyme substrate in terms of chemical structure and molecular geometry. Therefore, the inhibitor increases Km because it competes for the same active site as the substrate molecule. Competitive inhibition is generally reversible when sufficient substrate molecules are available to replace the inhibitor, that is, when the competitive inhibitor can bind reversibly. Thus, 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.

[0054] The term "specifically bind" as used herein refers to the interaction between a protein, such as α-Gal A, and a pharmacological chaperone, specifically the interaction with an amino acid residue of the protein that directly participates in contact with the pharmacological chaperone. The pharmacological chaperone specifically binds to a target protein, e.g., α-Gal A, and exerts a chaperone effect on proteins that are not part of the general group of related or unrelated proteins. The amino acid residue of the protein interacting with any given pharmacological chaperone may or may not be located within the protein's "active site." Specific binding can be evaluated through conventional binding assays or structural studies, e.g., co-crystallization, NMR, etc. The active site for α-Gal A is the substrate binding site.

[0055] "Deficient α-Gal A activity" refers to intracellular α-Gal A activity from patients that is below the normal range (using the same method) compared to activity in normal individuals who do not have or are not suspected of having Fabry or any other disease (especially blood disease).

[0056] The terms “enhance α-Gal A activity” or “increase α-Gal A activity,” as used herein, refer to increasing the amount of α-Gal A in a stable conformation in cells contacted with a pharmacological chaperone specific to α-Gal A compared to the amount in cells not contacted with a pharmacological chaperone specific to α-Gal A (preferably the same cell-type or the same cells, e.g., at a previous time point). The term also refers to increasing the trafficking of α-Gal A into lysosomes in cells contacted with a pharmacological chaperone specific to α-Gal A compared to the trafficking of α-Gal A not contacted with a pharmacological chaperone specific to a protein. These terms refer to both wild-type and mutant α-Gal A. In one embodiment, the increase in the amount of α-Gal A within the cell is measured by measuring the hydrolysis of an artificial substrate in a lysate from cells treated with PC. Increased hydrolysis indicates increased α-Gal A activity.

[0057] The term "α-Gal A activity" refers to the normal physiological function of wild-type α-Gal A in cells. For example, α-Gal A activity includes the hydrolysis of GL-3.

[0058] “Responders” are individuals diagnosed with or suspected of having a lysosomal storage disorder (LSD), such as Fabry disease, for example, whose cells exhibit sufficiently increased α-Gal A activity and / or improvement in symptoms or surrogate markers in response to contact with PC. Non-limiting examples of improvement in surrogate markers for Fabry are those disclosed in U.S. Patent Application Publication No. US 2010 / 0113517, in which lyso-GB3 and the full text thereof are incorporated herein by reference.

[0059] Non-limiting examples of improvement in surrogate markers for Fabry disease disclosed in US 2010 / 0113517 include: increased levels or activity of α-Gal A 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 myocardial cells and valvular fibroblasts; decreased plasma lyso-Gb3; reduced cardiac hypertrophy (particularly left ventricle), improvement of valvular insufficiency and arrhythmias; improvement of proteinuria; decreased urinary concentrations of lipids such as CTH, lactosylceramide, and ceramide, and increased urinary concentrations of glucosylceramide and sphingomyelin; absence of stacked inclusion bodies (zebra bodies) in glomerular epithelial cells; improvement of renal function; alleviation of hypohidrosis; absence of angiokeratosis; and hearing abnormalities, such as high-frequency sensorineural hearing loss, progressive hearing loss, sudden hearing loss, or improvement in tinnitus. Improvement in neurological symptoms includes prevention of transient ischemic attacks (TIAs) or stroke; and improvement in neuropathic pain manifesting as paresthesia (burning or tingling in the extremities). Another type of clinical marker that can be evaluated for Fabry disease is the prevalence of adverse cardiovascular findings. Common heart-related signs and symptoms of Fabry disease include left ventricular hypertrophy, valvular disease (particularly mitral prolapse and / or regurgitation), premature coronary artery disease, angina pectoris, myocardial infarction, conduction abnormalities, arrhythmias, and congestive heart failure.

[0060] The dose that achieves one or more of the responses mentioned above is the "therapeutic effective dose."

[0061] The phrase “pharmaceuticalally acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce undesirable reactions when administered to humans. In some embodiments, the term “pharmaceuticalally acceptable” as used herein means approved by federal or state regulatory agencies, or listed in the United States Pharmacopoeia or other generally accepted pharmacopoeias for animal use, and more particularly pharmacopoeias for human use. With respect to pharmaceutical carriers, the term “carrier” refers to a diluent, adjuvant, excipient, or vehicle administered with the compound. Such pharmaceutical carriers may be sterile liquids, such as water and oil. Water or aqueous saline solutions and aqueous dextrose and glycerol solutions are preferably used as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in the literature “Remington’s Pharmaceutical Sciences” by EW Martin, 18th Edition or other revisions.

[0062] The term “isolated” as used herein means that the reference material is removed from the environment in which it is typically found. Therefore, the isolated biological material may not have cellular components, that is, components of the cell in which the material is found or produced. In the case of nucleic acid molecules, the isolated nucleic acid comprises PCR products, mRNA bands on a gel, cDNA, or restriction fragments. In another embodiment, the isolated nucleic acid is preferably excised from the chromosome in which it may be found, and more preferably, is no longer connected to a non-regulating non-coding region or other gene located upstream or downstream of the gene contained by the isolated nucleic acid molecule when found on the chromosome. In another embodiment, the isolated nucleic acid lacks one or more introns. The isolated nucleic acid comprises a sequence inserted into a plasmid, cosmid, artificial chromosome, etc. Therefore, in certain embodiments, the recombinant nucleic acid is the isolated nucleic acid. The isolated protein may be associated with other proteins or nucleic acids or both that associate in the cell, or, if it is a membrane-associating protein, may be associated with the cell membrane. Isolated organelles, cells, or tissues are removed from the anatomical sites found in the organism. The isolated material may be purified, but does not need to be.

[0063] The term “enzyme replacement therapy” or “ERT” refers to the introduction of non-natural purified enzymes into individuals deficient in these enzymes. The proteins administered may be obtained from natural sources or through recombinant expression (as described in more detail below). The term also refers to the introduction of purified enzymes into individuals who otherwise require or benefit from the administration of purified enzymes, for example, individuals suffering from enzyme deficiency. The enzymes introduced may be purified recombinant enzymes produced in vitro, or proteins purified from isolated tissues or body fluids, such as placenta or animal milk, or from plants.

[0064] The term "ERT-naive patient" refers to a Fabry patient who has not received ERT or has not received ERT for at least 6 months prior to initiating migalastat therapy.

[0065] The term "ERT-experienced patient" refers to a Fabry patient who was receiving ERT immediately prior to initiating migalastat therapy. In some embodiments, the ERT-experienced patient received ERT for at least 12 months immediately prior to initiating migalastat therapy.

[0066] The terms "free base equivalent" or "FBE" as used herein refer to the amount of migalastart present in migalastart or its salts. In other words, the term "FBE" refers to the amount of migalastart free base, or the equivalent amount of migalastart free base provided by the salt of migalastart. For example, due to the weight of the hydrochloride salt, 150 mg of migalastart hydrochloride provides only 123 mg of migalastart in the free base form of migalastart. Different salts are expected to have different conversion factors depending on the molecular weight of the salt.

[0067] The term "migalastat" includes migalastat free base or a pharmaceutically acceptable salt thereof (e.g., migalastat HCl) unless specifically indicated otherwise.

[0068] The terms “mutation” and “variant” (e.g., as in “compliant mutation or variant”) refer to changes in the nucleotide sequence of a gene or chromosome. The two terms mentioned herein are typically used together (e.g., as in “mutation or variant”) to refer to changes in the nucleotide sequence mentioned in the preceding sentence. Where only one of the two terms is cited for some reason, it was intended to include the omitted term, and one should be understood as such. Additionally, the terms “compliant mutation” and “compliant variant” refer to mutations or variants compliant to PC therapy, e.g., mutations compliant to migalastat therapy. A specific type of compliant mutation or variant is the “HEK test compliant mutation or variant,” which is a mutation or variant determined to be compliant to migalastat therapy according to the criteria in the in vitro HEK test described herein and U.S. Patent No. 8,592,362 (the full text of which is incorporated herein by reference).

[0069] The terms “about” and “approximately” generally refer to an acceptable degree of error for a measured quantity, considering the nature or precision of the measurement. Typical and exemplary degrees of error are within 20 percent (%) of a given value or range of values, preferably within 10 percent, and more preferably within 5 percent. Alternatively, and particularly in biological systems, the terms “about” and “approximately” may refer to a value within 10 times a given value, preferably within 10 or 5 times, and more preferably within 2 times. Numerical quantities given herein are approximations unless otherwise noted, and the terms “about” or “approximately” mean that they can be inferred when not explicitly stated.

[0071] Fabry disease

[0072] Fabry disease is a rare, progressive, and devastating X-linked lysosomal storage disorder (LSD). Mutations in the GLA gene result in a deficiency of α-Gal A, a lysosomal enzyme necessary for glycosphingolipid metabolism. Decrease in α-Gal A activity, starting in childhood, leads to the accumulation of glycosphingolipids, including GL-3 and plasma lyso-Gb3, causing the symptoms of Fabry disease and life-limiting sequelae, including pain, gastrointestinal symptoms, renal failure, cardiomyopathy, cerebrovascular events, and premature death. Early initiation of therapy and lifelong treatment offer an opportunity to slow disease progression and extend life expectancy.

[0073] Fabry disease is traditionally divided into two main phenotypes, "classical" and "late-onset," but encompasses a spectrum of disease severity and age of onset. The classical phenotype is primarily attributed to men with low α-Gal A activity and undetectable early onset of renal, cardiac, and / or cerebrovascular findings. The late-onset phenotype is primarily attributed to men with higher residual α-Gal A activity and late onset of these disease findings. Heterozygous female carriers typically exhibit the late-onset phenotype, but may also display the classical phenotype depending on the pattern of X-chromosome inactivation.

[0074] Over 1,000 Fabry disease-causing GLA mutations have been identified. GLA mutations include, but are not limited to, missense, nonsense, and splicing mutations (in addition to small deletions and insertions), as well as larger gene rearrangements. Approximately 60% are missense mutations, resulting in a single amino acid substitution in the α-Gal A enzyme. Missense GLA mutations often lead to the production of abnormally folded and unstable forms of α-Gal A, and the majority are associated with the classical phenotype. Normal cellular quality control mechanisms in the ER block the translocation of these abnormal proteins into the lysosome and target premature degradation and clearance. Many missense mutant forms are targets of migalastat, an α-Gal A-specific pharmacological chaperone.

[0075] The clinical manifestations of Fabry disease span a broad spectrum of 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, and the majority of them are male. These patients experience disease affecting various organs, including the kidneys, heart, and brain; symptoms typically appear during adolescence and progress in severity until death in the 40s or 50s. Numerous recent studies suggest that there are many undiagnosed men and women with various Fabry disease symptoms that typically appear in adulthood, such as impaired heart or kidney function and stroke. Individuals with this type of Fabry disease, referred to as late-onset Fabry disease, tend to have higher residual α-Gal A levels than classic Fabry patients. Individuals with late-onset Fabry disease typically experience symptoms for the first time in adulthood and often present with symptoms concentrated in a single organ, such as left ventricular hypertrophy or progressive renal failure. Additionally, late-onset Fabry disease can also manifest as stroke of unknown etiology.

[0076] Proper diagnosis of Fabry disease is difficult because it is rare, affects multiple organs, and has a wide and heterogeneous age range of onset. For example, Fabry patients have progressive renal impairment, and untreated patients exhibit end-stage renal impairment by the age of 50. A deficiency in α-Gal A activity leads to the accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in many cell types, including renal cells. Gb3 accumulates in podocytes, epithelial cells, tubular cells of the distal tubules, and the loop of Henle. Impairment of renal function may manifest as proteinuria and a reduced glomerular filtration rate.

[0077] Furthermore, awareness among healthcare professionals is low, and misdiagnosis is frequent. The diagnosis of Fabry disease is most often confirmed when a patient exhibits symptoms, based on reduced α-Gal A activity in plasma or peripheral white blood cells (WBCs) along with mutation analysis. In women, diagnosis is significantly more difficult because enzyme identification in female carriers is less reliable due to random X-chromosome inactivation in some of the carrier's cells. For example, some obligate carriers (daughters of classically affected men) possess α-Gal A enzyme activity in the normal to very low range. Since carriers may have normal α-Gal A enzyme activity in their white blood cells, only the identification of α-Gal A mutations through genetic testing provides precise carrier identification and / or diagnosis.

[0078] In one or more embodiments, a mutant form of α-Gal A is considered to be compliant with migalastat, which is defined as exhibiting a relative increase of ≥1.20-fold (+10 μM migalastat) and an absolute increase of ≥3.0% of the wild type (WT) (+10 μM migalastat) when the mutant form of α-Gal A is expressed in HEK-293 cells (referred to as the “HEK assay”) according to Good Laboratory Practice (GLP)-validated in vitro assay (GLP HEK or migalastat compliant assay). These mutations are also referred to herein as “HEK assay compliant” mutations.

[0079] Previous screening methods for evaluating enzyme enhancement prior to the initiation of treatment have been provided. For example, assays using HEK-293 cells have been utilized in clinical trials to predict whether a given mutation responds to treatment with a pharmacological chaperone (e.g., migalastat). In this assay, a cDNA construct is generated. The corresponding α-Gal A mutant form is transiently expressed in HEK-293 cells. Subsequently, the cells are incubated with ± migalastat (17 nM to 1 mM) for 4 to 5 days. Afterward, α-Gal A levels are 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 inframe insertion / deletion mutations. Mutations previously identified as responding to PC (e.g., migalastat) using these methods are listed in U.S. Patent No. 8,592,362 (the full text of which is incorporated herein by reference).

[0081] Pharmacological chaperones

[0082] The binding of small molecule inhibitors of LSD-associated enzymes can increase the stability of both mutant enzymes and the 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 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 increased the stability of the enzymes in in vitro cells and thus increased the trafficking of the enzymes into lysosomes. Therefore, by increasing the amount of enzymes within the lysosomes, it is expected that the hydrolysis of enzyme substrates will increase. 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), enzyme proteins are delayed and degraded prematurely in the normal transport pathway (ER → Golgi apparatus → endosome → lysosome). Therefore, compounds that bind to mutant enzymes and increase their stability can act as "chaperones" for the enzymes and increase the amount that can exit the ER and move into the lysosomes. Additionally, because the 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 can be used to stabilize wild-type enzymes and increase the amount of enzymes that can exit the ER and be trafficked into the lysosomes.

[0083] In one or more embodiments, the pharmacological chaperone comprises migalastat or a salt thereof. Migalastat, a compound also known as 1-deoxygalactonozirimycin (1-DGJ) or (2R,3S,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol, is a compound having the following chemical formula:

[0084]

[0085] Migalasat free base

[0086] As discussed herein, pharmaceutically acceptable salts of migalastat may also be used in the present invention. When a salt of migalastat is used, the dosage of the salt will be adjusted so that the dose of migalastat received by the patient is equivalent to the amount received when using the free base of migalastat. An example of a pharmaceutically acceptable salt of migalastat is migalastat HCl:

[0087]

[0088] Migalastat HCl

[0089] Migalastat is a low molecular weight iminoglycan and an analog of terminal galactose of GL-3. In vitro and in vivo pharmacological studies have demonstrated that migalastat acts as a pharmacological chaperone that binds selectively and reversibly with high affinity to the active site of wild-type α-Gal A and specific mutant forms of α-Gal A, the genotype of which is referred to as the HEK assay-compliant mutant. Migalastat binding stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum, facilitating the proper trafficking of α-Gal A into lysosomes, which allows the dissociation of migalastat to reduce levels of GL-3 and other substrates. Approximately 30–50% of patients with Fabry disease possess the HEK assay-compliant mutant; most of these are associated with the classic phenotype of the disease.

[0090] HEK test-compliant mutations are at least those listed in the pharmacological reference table (e.g., migalastat products, e.g., Galafold). ® Includes (as cited on U.S. or international product labels). "Pharmacological reference tables" as used herein refer to specific mutations or variants of migalastat (e.g., galafold). ®Migalastat products (e.g., Galafold) that convey whether they respond to PC therapy ® It refers to any publicly accessible written or electronic record included on a product label within the packaging of ) or on a website accessible by a healthcare provider, and is not necessarily limited to written records presented in tabular form. In one embodiment of the invention, "pharmacological reference table" therefore refers to any information repository containing one or more conformational mutations or variants. An exemplary pharmacological reference table for HEK test conformational mutations is Galafold ® Galafold in various countries where use is approved ® A summary of product features and / or prescription information regarding [the product], or on websites such as www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com, the full text of each of which is incorporated herein by reference.

[0091] Most α-GAL mutations are missense mutations and most are located outside the catalytic site, but it is difficult to predict which mutations result in unstable enzymes that can be "restructured" by pharmacological chaperones (PCs) that stabilize the enzyme, and which mutations cannot be stabilized using PCs.

[0092] An exemplary pharmacological reference table for HEK test-compliant mutations is provided in Table 1 below. In one or more embodiments, if double mutations are present on the same chromosome (males and females), the patient is considered HEK test-compliant if the double mutation is present in one entry of Table 1 (e.g., D55V / Q57L). In some embodiments, if double mutations are present on different chromosomes (only in females), the patient is considered HEK test-compliant if one of the individual mutations is present in Table 1.

[0093] Table 1. HEK test conforming mutations

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0138] Medication, dosage form, and administration

[0139] In one or more embodiments, the Fabry patient is administered migalastat or a salt thereof at a frequency of 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 the salt of migalastat. In further embodiments, the salt of migalastat is migalastat hydrochloride. The administration of migalastat or a salt of migalastat is referred herein to as "migalastat therapy".

[0140] Accordingly, in one or more embodiments, the Fabry patient is administered migalastat or a salt thereof in a range of about 15 mg to about 300 mg, about 15 mg to about 250 mg, about 15 mg to about 200 mg, about 15 mg to about 150 mg, or about 15 mg to about 123 mg at a frequency of once every other day, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once every 7 days. In one or more embodiments, migalastat or a salt thereof is administered at a frequency of once every other day (also referred to as "QOD" or "Q48H"), once every 4 days (also referred to as "Q4D" or "Q96H"), or once every 7 days (also referred to as "Q7D" or "Q168H"). In some embodiments, the dosing interval may include any dosing interval greater than 48 hours between doses. For example, the dosing interval may include doses every 72, 96, 120, 144, or 168 hours.

[0141] In one or more embodiments, a Fabri patient takes migalastat FBE in an amount of about 15 mg to about 300 mg, about 15 mg to about 250 mg, about 15 mg to about 200 mg, about 15 mg to about 150 mg, about 15 mg to about 123 mg, about 15 mg to about 100 mg, about 15 mg to about 50 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 123 mg, about 50 mg to about 100 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 100 mg to about 150 mg, about 100 mg to It is administered in the range of about 123 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, about 150 mg to about 200 mg, about 200 mg to about 300 mg, about 200 mg to about 250 mg, or about 250 mg to about 300 mg at a frequency of once every other day, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once every 7 days.

[0142] In one or more embodiments, the Fabri patient receives about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 123 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, approx. 195 mg, approx. 200 mg, approx. 205 mg, approx. 210 mg, approx. 215 mg, approx. 220 mg, approx. 225 mg, approx. 230 mg, approx. 235 mg, approx. 240 mg, approx. 245 mg, approx. 250 mg, approx. 255 mg, approx. 260 mg, approx. 265 mg, approx. 270 mg, approx. 275 mg, approx. 280 mg, approx. 285 mg, approx. 290 mg, approx. 295 mg, or approx. 300 mg of migalastat FBE is administered at a frequency of once every other day, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once every 7 days.

[0143] Again, it is noted that 150 mg of migalastat hydrochloride is equivalent to 123 mg of the free base form of migalastat. Therefore, in one or more embodiments, the dose is 150 mg of migalastat hydrochloride or an equivalent dose of a salt other than migalastat or hydrochloride salt administered at a frequency of once every other day, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once every 7 days. In a further embodiment, the dose is 150 mg of migalastat hydrochloride administered at a frequency of once every other day. In another embodiment, the dose is 123 mg of the free base of migalastat administered at a frequency of once every other day.

[0144] In one or more embodiments, the Fabri patient takes migalastat hydrochloride in an amount of about 15 mg to about 300 mg, about 15 mg to about 250 mg, about 15 mg to about 200 mg, about 15 mg to about 150 mg, about 15 mg to about 123 mg, about 15 mg to about 100 mg, about 15 mg to about 50 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, about 50 mg to about 123 mg, about 50 mg to about 100 mg, about 100 mg to about 300 mg, about 100 mg to about 250 mg, about 100 mg to about 200 mg, about 100 mg to about 150 mg, about 100 It is administered in the range of mg to about 123 mg, about 150 mg to about 300 mg, about 150 mg to about 250 mg, about 150 mg to about 200 mg, about 200 mg to about 300 mg, about 200 mg to about 250 mg, or about 250 mg to about 300 mg at a frequency of once every other day, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once every 7 days.

[0145] In one or more embodiments, the Fabri patient receives about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 42 mg, about 45 mg, about 50 mg, about 55 mg, about 57 mg, about 60 mg, about 65 mg, about 67 mg, about 70 mg, about 75 mg, about 77 mg, about 79 mg, about 80 mg, about 85 mg, about 90 mg, about 94 mg, about 95 mg, about 97 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 128 mg, about 130 mg, about 135 mg, about 140 mg, about 144 mg, about 145 mg, about 150 mg, about 155 mg, approx. 160 mg, approx. 165 mg, approx. 170 mg, approx. 175 mg, approx. 180 mg, approx. 185 mg, approx. 190 mg, approx. 195 mg, approx. 200 mg, approx. 205 mg, approx. 210 mg, approx. 215 mg, approx. 220 mg, approx. 225 mg, approx. 230 mg, approx. 235 mg, approx. 240 mg, approx. 245 mg, approx. 250 mg, approx. 255 mg, approx. 260 mg, approx. 265 mg, approx. 270 mg, approx. 275 mg, approx. 280 mg, approx. 285 mg, approx. 290 mg, approx. 295 mg, or approx. 300 mg of migalastat hydrochloride once every other day, once every 3 days, once every 4 days, every 5 days It is administered at a frequency of once, once every 6 days, or once every 7 days.

[0146] In some embodiments, the patient's body weight is about 10 kg to about ≥50 kg, about 10 kg to about ≤50 kg, about 10 kg to about ≤45 kg, about 10 kg to about ≤40 kg, about 10 kg to about ≤35 kg, about 10 kg to about ≤30 kg, about 10 kg to about ≤25 kg, about 10 kg to about ≤20 kg, about 10 kg to about ≤15 kg, about 15 kg to about ≥50 kg, about 15 kg to about ≤50 kg, about 15 kg to about ≤45 kg, about 15 kg to about ≤40 kg, about 15 kg to about ≤35 kg, about 15 kg to about ≤30 kg, about 15 kg to about ≤25 kg, about 20 kg to about ≥50 kg, about 20 kg to about ≤50 kg, about 20 kg to Approx. ≤45 kg, approx. 20 kg to approx. ≤40 kg, approx. 20 kg to approx. ≤35 kg, approx. 20 kg to approx. ≤30 kg, approx. 20 kg to approx. ≤25 kg, approx. 25 kg to approx. ≥50 kg, approx. 25 kg to approx. ≤50 kg, approx. 25 kg to approx. ≤45 kg, approx. 25 kg to approx. ≤40 kg, approx. 25 kg to approx. ≤35 kg, approx. 25 kg to approx. ≤30 kg, approx. 30 kg to approx. ≥50 kg, approx. 30 kg to approx. ≤50 kg, approx. 30 kg to approx. ≤45 kg, approx. 30 kg to approx. ≤40 kg, approx. 30 kg to approx. ≤35 kg, approx. 35 kg to approx. ≥50 kg, approx. 35 kg to approx. ≤50 kg, approx. 35 kg to approx. ≤45 The range is approximately ≤40 kg, approximately 40 kg to approximately ≥50 kg, approximately 40 kg to approximately ≤50 kg, approximately 40 kg to approximately ≤45 kg, approximately 45 kg to approximately ≥50 kg, or approximately 45 kg to approximately ≤50 kg.

[0147] The administration of migalastat or its salt according to the present invention may be in a formulation suitable for any route of administration, but preferably in an oral form, such as a tablet, capsule, or solution. For example, a patient receives orally 25 mg, 40 mg, 50 mg, 60 mg, 75 mg, 80 mg, 100 mg, or 150 mg of migalastat hydrochloride (i.e., 1-deoxygalactonozirimycin hydrochloride) or an equivalent dose of a capsule containing a salt other than migalastat or hydrochloride. In another example, a patient receives orally 150 mg of migalastat hydrochloride or an equivalent dose of a capsule containing a salt other than migalastat or hydrochloride.

[0148] In various embodiments, the doses described herein relate to migalastat hydrochloride or equivalent doses of salts other than migalastat or hydrochloride salts. In some embodiments, these doses relate to the free base of migalastat. In alternative embodiments, these doses relate to salts 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".

[0149] Administration of migalastat or its salt may be for a specific period. In one or more embodiments, migalastat or its salt is administered for a duration of at least 28 days, e.g., at least 30, 60, or 90 days, or at least 4, 6, 8, 12, 16, 26, or 52 weeks, or at least 1, 2, 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 some embodiments, the migalastat regimen is at least about 4 weeks. In various embodiments, the migalastat regimen is a long-term migalastat regimen of at least about 2, 3, 4, or 5 years.

[0150] In some embodiments, PC (e.g., migalastat or a salt thereof) is administered orally. In one or more embodiments, PC (e.g., migalastat or a salt thereof) is administered by injection. PC may be accompanied by a pharmaceutically acceptable carrier, which may vary depending on the method of administration.

[0151] In one or more embodiments, PC (e.g., migalastat or a salt thereof) is administered as a monotherapy and may be in the form of, for example, tablets or capsules or a liquid, or in any form suitable for any route of administration including oral administration as an injectable sterile aqueous solution. In another embodiment, PC is provided as a dry lyophilized powder to be added to the formulation of a replacement enzyme during or immediately after reconstitution to prevent enzyme aggregation in vitro prior to administration.

[0152] When a PC (e.g., migalastat or a salt thereof) is formulated for oral administration, tablets or capsules may be manufactured by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods widely known in the art. Liquid formulations for oral administration may take the form, for example, of a solution, syrup, or suspension, or may be provided as a dry product to be combined with water or another suitable vehicle before use. These 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); emulsifiers (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 suitably contain buffering salts, flavoring agents, coloring agents, and sweeteners. Formulations for oral administration may be suitably formulated to provide controlled release of the active chaperone compound.

[0153] Pharmaceutical formulations of PC (e.g., migalastat or salts thereof) suitable for parenteral / injectable use generally comprise sterile aqueous solutions (if water-soluble), or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and fluid enough to be easily injected. It must be stable under manufacturing and storage conditions and preserved against the action of microorganisms, such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Suitable fluidity may be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action may be caused by various antibacterial and antifungal agents, e.g., parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, etc. In many cases, it would be appropriate to include isotonic agents, e.g., sugars or sodium chloride. Prolonged absorption of the injectable composition may be caused by the use of absorption-delaying agents, e.g., aluminum monostearate and gelatin in the composition.

[0154] Sterile injectable solutions are prepared by incorporating the required amount of PC (e.g., migalastat or its salt) and purified enzyme (if present) into a suitable solvent along with the various other components listed above, and then performing filtration or terminal sterilization as necessary. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a base dispersion medium and other necessary components among those listed above. For sterile powders for the preparation of sterile injectable solutions, a preferred manufacturing method is vacuum drying and freeze-drying techniques to produce a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0155] The formulation may contain excipients. Pharmaceutically acceptable excipients that may be included in the formulation are buffers, e.g., citrate buffers, phosphate buffers, acetate buffers, bicarbonate buffers, amino acids, urea, alcohols, ascorbic acid, and phospholipids; proteins, e.g., serum albumin, collagen, and gelatin; salts, e.g., EDTA or EGTA, and sodium chloride; liposomes; polyvinylpyrrolidone; sugars, e.g., dextran, mannitol, sorbitol, and glycerol; propylene glycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol; glycine or other amino acids; and lipids. A buffer system for use with the formulation comprises citrate; acetate; bicarbonate; and phosphate buffers. Phosphate buffers are a preferred embodiment.

[0156] The route of administration of chaperone compounds may be oral or parenteral, for example, intravenous, subcutaneous, intra-arterial, intraperitoneal, ocular, intramuscular, buccal, rectal, vaginal, orbital, intracerebral, intradermal, intracranial, spinal cord, intraventricular, intradural, intracerebellar, intracapsular, intrapulmonary, intranasal, transmucosal, transdermal, or via inhalation.

[0157] Administration of the above-described parenteral formulation of a chaperone compound may be carried out by periodic injection of a bolus of the formulation, or by intravenous or intraperitoneal administration from a reservoir located externally (e.g., IV bag) or internally (e.g., biodegradable implant).

[0158] Embodiments relating to pharmaceutical formulations and administration may be combined with any other embodiments of the present invention, e.g., methods for treating a patient with Fabry disease, methods for treating an ERT-naive Fabry patient, methods for treating an ERT-experienced Fabry patient, methods for reducing the risk of CBV events, methods for reducing the risk of composite clinical outcomes, methods for evaluating symptoms or outcomes of a patient or group of patients, methods for evaluating a therapeutic regimen, methods for enhancing α-Gal A in a patient diagnosed with or suspected of having Fabry disease, the use of a pharmacological chaperone for α-Gal A for the manufacture of a medicine to treat a patient diagnosed with Fabry disease, or the use of a pharmacological chaperone for α-Gal A for use in treating a patient diagnosed with Fabry disease, as well as embodiments relating to compliant mutations, PCs, and suitable dosages thereof.

[0159] In one or more embodiments, a PC (e.g., migalastat or a salt thereof) is administered in combination with an ERT. The 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 mentioned above. After infusion, the exogenous enzyme is expected to be absorbed by tissues via non-specific or receptor-specific mechanisms. Generally, absorption efficiency is not high, and the circulation time of the exogenous protein is short. Furthermore, the exogenous protein is unstable and undergoes rapid intracellular degradation, as well as having the potential for immunological adverse reactions in subsequent treatment. In one or more embodiments, a chaperone is administered concurrently with an alternative enzyme (e.g., alternative α-Gal A). In some embodiments, the chaperone is co-formulated with an alternative enzyme (e.g., alternative α-Gal A).

[0160] In one or more embodiments, the patient is switched from ERT to migalastat therapy. In some embodiments, a patient undergoing ERT is identified, the patient's ERT is discontinued, and the patient begins receiving migalastat therapy. Migalastat therapy may follow any method described herein. In various embodiments, the patient has some degree of renal impairment, e.g., mild, moderate, or severe renal impairment.

[0162] Administration of Migalastat

[0163] In some embodiments, migalastat or its salt is administered to adult patients. In some embodiments, the age of the adult patient is ≥18 years. In some embodiments, migalastat or its salt is administered to adolescent patients. In some embodiments, the age of the adolescent patient is in the range of 12 to <18 years, 13 to <18 years, 14 to <18 years, 15 years to <18 years, 16 to <18 years, 17 to <18 years, 12 to ≤17 years, 13 to ≤17 years, 14 to ≤17 years, 15 years to ≤17 years, 16 to ≤17 years, 12 to ≤16 years, 13 to ≤16 years, 14 to ≤16 years, 15 years to ≤16 years, 12 to ≤15 years, 13 to ≤15 years, 14 to ≤15 years, 12 to ≤14 years, 13 to ≤14 years, or 12 to ≤13 years.

[0164] In some embodiments, migalastat or its salt is administered to patients with a body weight in the range of <15 kg to ≥45 kg, 15 kg to <25 kg, 25 kg to <35 kg, or 35 kg to <45 kg. In some embodiments, migalastat or its salt is administered to patients with a body weight of <15 kg. In some embodiments, migalastat or its salt is administered to patients with a body weight of ≥45 kg.

[0165] In some embodiments, about 25 mg of migalastat or its salt is administered to patients with a body weight of <15 kg. In some embodiments, about 50 mg of migalastat or its salt is administered to patients with a body weight in the range of 15 kg to <25 kg. In some embodiments, about 75 mg of migalastat or its salt is administered to patients with a body weight in the range of 25 kg to <35 kg. In some embodiments, about 75 mg of migalastat or its salt is administered to patients with a body weight in the range of 35 kg to <50 kg.

[0166] In some embodiments, migalastat or its salt is administered at a first frequency for a first period, and then at a second frequency for a second period. The first frequency is greater than (i.e., more frequent) than the second frequency. The first and second frequencies may be any dosing intervals disclosed herein. In some embodiments, the first frequency is every other day, and the second frequency is every 3, 4, 5, 6, or 7 days. In some embodiments, the first frequency is every 4 days, and the second frequency is every 5, 6, or 7 days.

[0167] In some embodiments, migalastat or its salt is administered at a first frequency for a first period, then at a second frequency for a second period, and then at a third frequency for a third period. The first frequency is greater than (i.e., more frequent) than the second frequency, and the second frequency is greater than the third frequency. For example, in some embodiments, migalastat or its salt is administered at a first frequency once every other day for a first period, then migalastat or its salt is administered at a second frequency once every four days for a second period, and then migalastat or its salt is administered at a third frequency once every seven days for a third period.

[0169] Administration of Migalastat without caffeine

[0170] As mentioned above and described in more detail in the following examples, caffeine was found to have a surprisingly significant effect on the pharmacokinetics of migalastat. Accordingly, in some embodiments, the patient does not consume caffeine within a specific time interval after administering a formulation containing migalastat or a salt thereof. In various embodiments, this time interval includes refraining from caffeine for at least 30 minutes, at least 60 minutes (1 hour), at least 90 minutes (1.5 hours), at least 2 hours, at least 2.5 hours, at least 3 hours, or at least 4 hours before administering migalastat or a salt thereof, and for at least 30 minutes, at least 60 minutes (1 hour), at least 90 minutes (1.5 hours), at least 2 hours, at least 2.5 hours, at least 3 hours, or at least 4 hours after administering migalastat or a salt thereof.

[0171] In some embodiments, the patient does not consume caffeine within a time interval between at least one hour before administering migalastat or its salt and at least one hour after administration, that is, the patient does not consume caffeine within about one hour of administering a formulation containing migalastat or its salt.

[0172] In some embodiments, the patient does not consume caffeine within a time interval between at least 2 hours before administering migalastat or its salt and at least 1 hour after administration.

[0173] In some embodiments, the patient does not consume caffeine within a time interval between at least 2 hours before administering migalastat or its salt and at least 2 hours after administration, that is, the patient does not consume caffeine within about 2 hours of administering a formulation containing migalastat or its salt.

[0174] In some embodiments, the patient does not consume caffeine within a time interval between at least 3 hours before administering migalastat or its salt and at least 2 hours after administration.

[0175] In some embodiments, the patient does not consume caffeine within a time interval between at least 3 hours before administering migalastat or its salt and at least 3 hours after administration, that is, the patient does not consume caffeine within about 3 hours of administering a formulation containing migalastat or its salt.

[0176] In some embodiments, the patient consumes caffeine outside of the caffeine abstaining time interval. For example, if the caffeine abstaining time interval is at least 2 hours before administration of migalastat or its salt and at least 2 hours after administration, in some embodiments, the patient consumes caffeine at least 2 hours before administration of migalastat or its salt and / or at least 2 hours after administration. In various embodiments, the patient consumes caffeine at least 30 minutes, at least 60 minutes (1 hour), at least 90 minutes (1.5 hours), at least 2 hours, at least 2.5 hours, at least 3 hours, or at least 4 hours before administration of migalastat or its salt. In various embodiments, the patient consumes caffeine at least 30 minutes, at least 60 minutes (1 hour), at least 90 minutes (1.5 hours), at least 2 hours, at least 2.5 hours, at least 3 hours, or at least 4 hours after administration of migalastat or its salt.

[0177] In some embodiments, not consuming caffeine within a specific time interval following the administration of a formulation containing migalastat or a salt thereof improves the pharmacokinetics of migalastat, e.g., the area under the migalastat curve (AUC) and / or the maximum plasma concentration (C max It provides avoidance of a reduction in ). In some embodiments, the patient receives AUC and C for migalastat. max To avoid a reduction of approximately 57% and 60%, respectively, do not consume caffeine within 2 hours of administering a formulation containing migalastat or its salt.

[0178] In some embodiments, the patient fasts during the time interval of refraining from caffeine. In some embodiments, the patient does not consume food for at least 2 hours before administering migalastat or its salt and for at least 2 hours after administration, and the patient does not consume caffeine for at least 2 hours before administering migalastat or its salt and for at least 2 hours after administration.

[0179] In some embodiments, the patient fasts for a different time interval from the time interval during which caffeine is abstained.

[0180] In some embodiments, the patient does not consume a caffeine-containing beverage during the time interval. In some embodiments, the caffeine-containing beverage includes coffee, espresso, tea, caffeine-containing energy drinks, and caffeine-containing soda.

[0181] In some embodiments, the patient consumes a caffeine-free beverage during time intervals when caffeine is not consumed. Examples of suitable caffeine-free beverages include, but are not limited to, water (plain, flavored, sweetened), fruit juice without pulp, and caffeine-free carbonated beverages. In some embodiments, the caffeine-free beverage includes a sweetened beverage. In some embodiments, the caffeine-free beverage includes an artificially sweetened beverage. In some embodiments, the artificial sweetener includes aspartame or acesulfame potassium. Other artificial sweeteners and / or sugar substitutes include, but are not limited to, sucralose, stevia, and saccharin. In some embodiments, the caffeine-free and / or low-caffeine beverage includes decaffeinated coffee or decaffeinated tea.

[0182] In some embodiments, rather than abstaining from caffeine completely, the patient consumes only a small amount of caffeine during time intervals when caffeine is not consumed. In various embodiments, the patient limits total caffeine intake during time intervals when caffeine is not consumed to less than 200 mg, less than 190 mg, less than 180 mg, less than 170 mg, less than 160 mg, less than 150 mg, less than 140 mg, less than 130 mg, less than 120 mg, less than 110 mg, less than 100 mg, less than 95 mg, less than 90 mg, less than 85 mg, less than 80 mg, less than 75 mg, less than 70 mg, less than 65 mg, less than 60 mg, less than 55 mg, less than 50 mg, less than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, less than 15 mg, less than 10 mg, less than 5 mg, less than 4 mg, less than 3 mg, less than 2 mg, or less than 1 mg.

[0183] Another aspect of the present invention is the pharmacokinetics of migalastat (e.g., AUC and C max This relates to informing the patient about the effects of caffeine consumption on ) and / or instructing the patient not to consume caffeine within a specific time interval of migalastat administration. In some embodiments, this information and / or instructions are provided to the patient orally by a healthcare provider. In some embodiments, this information and / or instructions are provided to the patient in written form, such as prescription information, product labels, product features, product monographs, patient information, etc. In various embodiments, this information and / or instructions are Galafold ® Galafold in various countries where use is approved ®Product features and / or prescription information regarding, or provided on websites such as www.galafoldamenabilitytable.com or www.fabrygenevariantsearch.com, the full text of each of which is incorporated herein by reference.

[0184] In some embodiments, information and / or instructions include one or more of the following:

[0185] · Pharmacokinetic studies showed that the administration of coffee containing approximately 190 mg of caffeine resulted in a significant reduction in systemic exposure to migalastat compared to water (57% AUC 0-∞ It showed an average decrease of and an average decrease of Cmax by 60%.

[0186] · A single-dose, 6-way crossover pharmacokinetic study was performed in 20 healthy subjects to evaluate the plasma bioavailability of 150 mg migalastat HCl capsules when administered with coffee and sugary beverages compared to when administered with water. The absorption rate of migalastat (t max ...was not affected by the administration of coffee or sugary beverages compared to water. However, the consumption of 280 mL of coffee containing approximately 190 mg of caffeine at the time of administration resulted in a significant reduction in systemic exposure to migalastat compared to water (as much as 57% AUC 0-∞ The average decrease of and 60% of C max (average decrease of). The bioavailability of migalastat compared to water is natural (sucrose: 8027 ng·h / mL AUC 0-∞ and 1265 ng / mL C max ) and artificial (aspartame or acesulfame K: 9075 ng.h / mL, 8641 ng.h / mL AUC, respectively) 0-∞ and 1374 ng / mL, 1225 ng / mL C max ) Sweetener (8613 ng.h / mL AUC 0-∞ and 1328 ng / mL C maxIt was not significantly different when administered with ).

[0187] In addition to not consuming food at least 2 hours before taking migalastat and 2 hours after taking it, caffeine must not be consumed during this period.

[0188] · No form of caffeine should be consumed during the 4-hour fasting period.

[0189] · Consuming caffeine-containing beverages or other products containing caffeine may affect the way migalastat works.

[0190] · Water (plain, flavored, sweetened), fruit juice without pulp, and caffeine-free carbonated beverages may be consumed during a 4-hour fasting period.

[0191] · Migalastat reduces exposure by approximately 40% when taken with food, so it should be taken on an empty stomach. To ensure a minimum 4-hour fast, you must not consume food at least 2 hours before taking Migalastat and 2 hours after taking it. During this period, you may consume clear liquids, such as water, fruit juice without pulp, carbonated drinks, or tea or coffee without milk or cream.

[0193] Monitoring of Lyso-Gb3 and Migalastat levels

[0194] Lyso-Gb3 (globotriaosylsphingosine) can be monitored to determine whether substrates are being cleared from the body of Fabry patients. Higher levels of lyso-Gb3 correlate with higher levels of substrates. If the patient is successfully treated, lyso-Gb3 levels are expected to decrease. One dosing regimen for Fabry disease is to administer about 20 mg to about 300 mg of the FBE of migalastat or its salt to the patient every other day.

[0195] In some embodiments, the method further includes the step of measuring the migalastat level. In one or more embodiments, the migalastat concentration (e.g., ng / mL) is measured. In some embodiments, the total area under the curve (AUC 0-∞ ) is measured. In one or more embodiments, the lowest concentration of migalastat reached before the next dose (C 최저 ) is measured.

[0196] Migalastat levels can be measured by methods known in the relevant art. For example, when measuring migalastat from a tissue sample, the tissue aliquot can be homogenized using a homogenizer (e.g., FastPrep-24 from MP Biomedical, Irvine, California, USA) (7 μL of water per 1 mg of tissue). Then, a microcentrifuge tube containing 100 μL of tissue homogenate or 50 μL of plasma can be spiked with a 500 ng / mL 13C d2-AT1001 HCl internal standard (manufactured by MDS Pharma Services). Afterward, a volume of 600 μl of 5 mM HCl in 95 / 5 MeOH:H2O is added, the tube is vortexed for 2 minutes, and then centrifuged at 21,000 xg for 10 minutes at room temperature. Subsequently, the supernatant is collected in a clean 96-well plate, diluted with 5 mM HCl in dH2O, and applied to a 96-well solid-phase extraction (SPE) plate (Waters Corp., Milford, Massachusetts, USA). After several washing steps and elution into a clean 96-well plate, the extract is dried under N2 and reconstituted with mobile phase A. Subsequently, the migalastat levels can be determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS) (e.g., LC: Shimadzu; MS / MS: ABSciex API 5500 MS / MS). Liquid chromatography was performed on a Halo HILIC column (150 x 4.6 mm, 2.7 μm) (Advanced Materials Technology, Inc.) at a flow rate of 0.7 mL / min using an ACN:water:formate binary mobile phase system (Mobile Phase A: 5 mM ammonium formate, 0.5% formic acid in 95:5 ACN:water; Mobile Phase B: 5 mM ammonium formate, 0.5% formic acid in 5:47.5:47.5 ACN:MeOH:water).This can be performed using 5% formic acid. MS / MS analysis can be performed under APCi cation mode. The same procedure can be followed for the determination of migalastat in plasma, except for the absence of homogenization. The following precursor ion → product ion transition can be monitored: mass / charge (m / z) 164.1 → m / z 80.1 for migalastat and m / z 167.1 → m / z 83.1 for the internal standard. A 12-point calibration curve and quality control samples can be prepared. Subsequently, the ratio of the area under the curve for migalastat to the area under the curve for the internal standard is determined, and the final concentration of migalastat in each sample is calculated using a linear least squares fitting equation applied to the calibration curve. To derive the approximate molar concentration, 1 gram of tissue can be estimated to have a volume of 1 mL.

[0197] In some embodiments, samples may be taken at 0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and / or 168 hours after administration. In some embodiments, the concentration of migalastat is measured at 48 hours after administration. In some embodiments, administration of the second period begins after a migalastat concentration greater than about 5, 10, 15, 20, 25, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, or 200 ng / mL is measured at 48 hours after the administration of migalastat during the first period is measured.

[0198] In some embodiments, Lyso-Gb3 may be measured using validated assays via methods known in the relevant art. As with migalastat, lyso-Gb3 levels may be determined using liquid chromatography-tandem mass spectrometry (LC-MS / MS) (e.g., LC: Shimadzu; MS / MS: ABSciex API 5500 MS / MS). For example, one process for measuring plasma lyso-Gb3 is [Hamler, Rick, et al. “Accurate quantitation of plasma globotriaosylsphingosine (lyso-Gb3) in normal individuals and Fabry disease patients by liquid chromatography-tandem mass spectrometry (LC-MS / MS).” Molecular Genetics and Metabolism It is described in Volume 114.2 (2015):S51. In one or more embodiments, lyso-Gb3 is measured from a sample of a patient's urine.

[0200] Capacity adjustment

[0201] In some embodiments, the frequency of administration of migalastat or its salt is adjusted in response to changes in the patient's eGFR. In an exemplary embodiment, the patient's eGFR is 60 mL / min / 1.73 m 2 Less than, 45 mL / min / 1.73 m 2 Less than, 30 mL / min / 1.73 m 2 Less than or equal to 15 mL / min / 1.73 m 2 If it decreases below a certain level, the frequency of administration may be reduced. In some embodiments, the patient's eGFR is 60 mL / min / 1.73 m 2 Less than, 45 mL / min / 1.73 m 2 Less than, 30 mL / min / 1.73 m 2 Less than or equal to 15 mL / min / 1.73 m 2 If reduced to less than [amount], the patient does not receive migalastat or its salt.

[0202] Migalastat concentrations can be measured from plasma samples at various times to monitor clearance from the body. A clinically relevant increase in C trough suggests a significant accumulation of plasma migalastat concentrations. If migalastat is not sufficiently cleared from the body before the next dose, levels of migalastat may accumulate and potentially cause a depressant effect. Therefore, in one or more embodiments, changes in dosing frequency [indicate] normal renal function C 최저 Compared to C 최저 It occurs after a 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0-fold increase.

[0203] In one or more embodiments, changes in dosing frequency are normal renal function AUC 0-∞ AUC compared to 0-∞ It occurs after a 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3.0-fold increase.

[0204] In some embodiments, the method further comprises the step of measuring lyso-Gb3 in one or more plasma samples from a patient. A first baseline lyso-Gb3 level may be determined during a first period. As used herein, "baseline lyso-Gb3 level" refers to the lowest plasma lyso-Gb3 value measured during a given period or regimen. Therefore, if the lyso-Gb3 level increases significantly above the baseline lyso-Gb3 level, this may indicate progression of renal disease and / or inadequate clearance of migalastat. Therefore, in additional embodiments, administration of the second period is initiated after an increase above the first baseline lyso-Gb3 level (e.g., at least about 20, 25, 30, 33, 35, 40, 45, or 50% and / or 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, or 3 nM) is measured. An increase of 33% and / or 2 nM from baseline in plasma lyso-Gb3 was considered clinically relevant based on Phase 3 data from Fabry patients signaling inhibition-induced migalastat exposure from a decline in renal function and / or progression of the disease state. Lyso-Gb3 levels may be measured at varying frequencies (e.g., once every about 2, 3, 4, or 5 months). Once the medication regimen begins, it is thought that it takes about 3 months to establish baseline lyso-Gb3 levels.

[0205] In some embodiments, administration of the second period may be initiated 48 hours after the administration of migalastat during the first period is measured, after an increase above the first baseline lyso-Gb3 level of at least about 30 or 33% and / or migalastat greater than 2 nM and / or about 50 ng / mL is measured. In some embodiments, administration of the second period is initiated 48 hours after the administration of migalastat during the first period is measured, after an increase above the first baseline lyso-Gb3 level of at least about 30 or 33% and / or migalastat greater than 2 nM and / or about 50 ng / mL is measured, or compared to normal renal function during the first period, after an AUC 0-∞ and / or C 최저 It can start after an increase of more than 1.5 times.

[0207] Examples

[0208] Example 1: Study of the effects of caffeine and sweeteners on the pharmacokinetics of migalastat

[0209] This example describes the AT1001-045 study, an open-label study of the bioavailability, safety, and tolerance of migalastat combined with caffeine and a sweetener.

[0211] Destination and Endpoint

[0212] The primary objective was to evaluate the plasma bioavailability of 150 mg migalastat HCl capsules in caffeine-containing beverages, sucrose beverages, caffeine-containing and sucrose combination beverages, aspartame artificial sweetener beverages, and acesulfame potassium artificial sweetener beverages in healthy subjects compared to water.

[0213] The secondary objective was to evaluate the safety and tolerance of migalastat HCl in healthy subjects.

[0214] The first terminus is C max , AUC 0-t and AUC 0-∞The ANOVA comparison of interest between each test treatment and reference treatment was the comparison of interest. The comparisons of interest were the point estimate ratios and the lower / upper 90% confidence intervals.

[0216] Research Design

[0217] This was a single-center, single-dose, randomized, open-label, 6-way crossover study. Each subject received a single oral dose of 150 mg of migalastat HCl for each of the six periods. A schematic diagram of the study is shown in Figure 4.

[0218] In a random order, each subject received a caffeine-containing beverage, a sucrose drink, a caffeine-containing and sucrose combination drink, an aspartame artificial sweetener drink, an acesulfame potassium artificial sweetener drink, or a 150 mg migalastat HCl capsule with water.

[0219] All study treatments were administered on a fasting state (overnight + 4 hours after administration).

[0220] Each single dose administration was followed by a 72-hour PK sampling period, which also served as an inter-treatment washout interval.

[0221] The subject resided for the duration of six treatment periods through period 6 72-hour blood samples (approximately 19 days, including day -1).

[0222] Approximately 7 days (Day 23) after period 6 administration, the subject returned to the clinic for a follow-up visit.

[0223] The total duration of the study, including screening, was approximately 7.5 weeks.

[0224] The subjects whose research was discontinued were not replaced.

[0225] Appropriate migalastat exposure ratios (Cmax and AUC) with corresponding 90% confidence intervals will be used to perform the comparison of interest:

[0226] · Caffeine (Test) vs. Water (Reference)

[0227] · Sucrose (Test) vs. Object (Reference)

[0228] · Caffeine + Sucrose (Test) vs. Water (Reference)

[0229] · Aspartame (Test) vs. Water (Reference)

[0230] · Acesulfame K (Test) vs. Water (Reference)

[0232] Study group, sample size, and volume

[0233] Study group: Healthy male and female subjects aged 18 to 45.

[0234] Sample size: 20 subjects balanced by gender.

[0235] Dosage: A single 150 mg capsule of migalastat hydrochloride provided as Galafold®.

[0237] Preparation for test treatment

[0238] The following test treatment was prepared:

[0239] Caffeine-containing beverage: 8 oz of caffeine-containing tea; no additives; administered warm (40 to 50°C) and consumed within 10 minutes.

[0240] Sucrose Drink: 8 oz sucrose solution prepared with 26 grams of sucrose, cooled before drug administration and consumed within 10 minutes.

[0241] · Equivalent to the sucrose content in a single 8 oz serving of sugarcane sugar-containing Coca-Cola®

[0242] Caffeine-containing + Sucrose Drink: 8 oz caffeine-containing / sucrose beverage, chilled before drug administration and consumed within 10 minutes (e.g., Jolt®)

[0243] Aspartame: 8 oz aspartame solution prepared with 125 mg aspartame, cooled before drug administration and consumed within 10 minutes.

[0244] · Equivalent to the aspartame content in one 8 oz can of Diet Coke®

[0245] Acesulfame K: 8 oz acesulfame K solution prepared with 30 mg acesulfame K, cool before drug administration and consume within 10 minutes.

[0246] · Equivalent to the acesulfame K content in one 8 oz can of Diet Coke® or Coca-Cola® Zero Sugar

[0248] result

[0249] The pharmacokinetics of migalastat for each treatment are shown in Fig. 5 and Table 2 below. For a treatment to be considered bioequivalent to water, the 90% confidence interval must be within 80% to 125% of the value for water.

[0250] Table 2 - Migalastat Pharmacokinetics

[0251]

[0252] As can be seen from Figure 5 and Table 2, the artificial sweeteners acesulfame K and aspartame are biologically equivalent to water. Therefore, in some embodiments, a drink containing these artificial sweeteners may be administered with migalastat.

[0253] Sucrose was very close to biologically equivalent; the average difference in AUC was only an 8% decrease in the case of sucrose, which is not considered clinically relevant. Therefore, in some embodiments, a drink containing sucrose may be administered together with migalastat.

[0254] There was a major caffeine-migalastat interaction; C max ...was reduced by 60%, and the AUC was reduced by 57% in the case of caffeine alone; a similar reduction was observed in the case of caffeine + sucrose. Therefore, in some embodiments, migalastat should not be administered with caffeine-containing beverages.

[0255] The patents and scientific literature cited herein establish the knowledge available to a person skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are incorporated by reference. All other published references, documents, manuscripts, and scientific literature cited herein are incorporated by reference.

[0256] Although the present invention has been illustrated and described with reference to particularly preferred embodiments thereof, those skilled in the art will understand that various modifications in form and detail may be made without departing from the scope of the invention as set forth in the appended claims.

[0257] 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 invention. It is intended that various modifications and alterations consistent with the description in whole and readily apparent to a person skilled in the art are included. The appended claims should not be limited by the specific embodiments presented in the embodiments, but should be given the broadest possible interpretation consistent with the description in whole.

[0258] Patents, patent applications, publications, product descriptions, GeneBank access numbers, and protocols are incorporated herein by reference throughout this application, the full text of which is incorporated herein by reference for all purposes.

Claims

Claim 1 A formulation for use in a method to avoid a decrease in AUC and Cmax for migalastat, comprising a therapeutically effective dose of migalastat or a salt thereof for treating Fabry disease in a patient, wherein the formulation is administered orally to the patient, and the patient does not consume caffeine within a time interval between at least 2 hours before administering the formulation and at least 2 hours after administering the formulation. Claim 2 delete Claim 3 A formulation according to claim 1, wherein the reduction in AUC and Cmax for migalastat is 57% and 60%, respectively. Claim 4 delete Claim 5 A formulation according to claim 1, wherein the patient does not consume caffeine within a time interval between at least 3 hours before administering the formulation containing migalastat or a salt thereof and at least 2 hours after administration. Claim 6 A formulation according to claim 1, wherein the patient does not consume caffeine within a time interval between at least 3 hours before administering the formulation containing migalastat or a salt thereof and at least 3 hours after administration. Claim 7 A formulation according to claim 1 in which the patient consumes caffeine outside of the time interval during which caffeine is avoided. Claim 8 A formulation according to claim 1, further comprising administering caffeine to the patient at least 4 hours prior to administering the formulation containing migalastat or a salt thereof. Claim 9 A formulation according to claim 1, further comprising administering caffeine to the patient at least 4 hours after administering a formulation containing migalastat or a salt thereof. Claim 10 A formulation according to claim 1, wherein the patient consumes a caffeine-free beverage during the time interval of refraining from caffeine. Claim 11 A formulation according to claim 1, wherein the patient fasts during the time interval of refraining from caffeine. Claim 12 A formulation according to claim 1, wherein the patient fasts within a time interval between at least 2 hours before administering the formulation containing migalastat or a salt thereof and 2 hours after administration. Claim 13 A formulation according to claim 1 in which the salt of migalastat is migalastat hydrochloride. Claim 14 A formulation according to claim 1, wherein the therapeutically effective dose of migalastat or its salt is in the range of 100 mg to 150 mg every other day. Claim 15 A formulation of claim 1 in which the therapeutically effective dose of migalastat or its salt is 123 mg of free base equivalent (FBE) every other day. Claim 16 A formulation according to claim 1, wherein the therapeutically effective dose of migalastat hydrochloride is 150 mg every other day.

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