Methods of treating fabry patients having renal impairment

Abstract

To provide a method for treatment of Fabry disease in a patient having renal impairment.SOLUTION: Provided are methods for treatment of Fabry disease in a patient having renal impairment and / or elevated proteinuria. Certain methods comprise administering to the patient about 100 to about 150 mg free base equivalent of migalastat or a salt thereof at a frequency of once every other day. Certain methods also provide for stabilization of renal function, reduced left ventricular mass index, reduced plasma globotriaosylsphingosine, and / or increased α-galactosidase A activity in the patient.SELECTED DRAWING: Figure 11

Description

[Technical Field]

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

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

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

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

[0005] Several approaches to treating Fabry disease exist. One approved therapy for Fabry disease is enzyme replacement therapy (ERT), which typically involves intravenous infusion of a purified form of the corresponding wild-type protein. Two α-Gal A preparations are currently available for the treatment of Fabry disease: agalsidase alfa (Replagal®, Shire Human Genetic Therapies) and agalsidase beta (Fabrazyme®; Sanofi Genzyme Corporation). However, ERT has several drawbacks. One of the major complications of ERT is the rapid degradation of the injected protein, which leads to multiple, expensive, high-dose infusions. ERT also has several caveats, including the difficulty of large-scale production, purification, and storage of properly folded protein; the availability of glycosylated native protein; the development of anti-protein immune responses; and the inability of the protein to cross the blood-brain barrier and alleviate central nervous system pathology (i.e., low bioavailability). Additionally, replacement enzymes cannot penetrate the heart or kidney in sufficient quantities to reduce substrate accumulation in renal podocytes or cardiac myocytes, which is prominent in Fabry lesions.

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

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

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

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

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

[0011] Various aspects of the present invention relate to the treatment of Fabry patients with renal dysfunction and / or hyperproteinuria with migalastat, which may include stabilizing the patient's renal function, reducing left ventricular mass index (LVMi), reducing plasma globotriaosylsphingosine (lyso-Gb3), and / or increasing α-Gal A activity.

[0012] One aspect of the invention relates to a method for treating Fabry disease in a patient with impaired renal function, comprising administering to the patient an effective amount of migalastat or a salt thereof once every other day. In one or more embodiments, the effective amount is about 100 mg to about 150 mg free base equivalent (FBE).

[0013] In one or more embodiments, the patient has mild or moderate renal impairment.

[0014] In one or more embodiments, the patient has mild renal impairment.

[0015] In one or more embodiments, the patient has moderate renal impairment.

[0016] In one or more embodiments, the patient has severe renal impairment.

[0017] In one or more embodiments, the patient is an ERT-experienced patient.

[0018] In one or more embodiments, the patient is an ERT-naive patient.

[0019] In one or more embodiments, the patient has a proteinuria level of less than 100 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0020] In one or more embodiments, the patient has a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0021] In one or more embodiments, the patient has a proteinuria level greater than 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0022] In one or more embodiments, migalastat or a salt thereof enhances a-Gal A activity in the patient. In one or more embodiments, the a-Gal A activity is white blood cell (WBC) a-Gal A activity.

[0023] In one or more embodiments, administration of migalastat or a salt thereof is effective to reduce the patient's LVMi.

[0024] In one or more embodiments, administration of migalastat or a salt thereof is effective to stabilize plasma lyso-Gb3 in the patient.

[0025] In one or more embodiments, administration of migalastat or a salt thereof is effective in stabilizing renal function in the patient.

[0026] In one or more embodiments, the effective amount is about 123 mg FBE.

[0027] In one or more embodiments, the effective amount is about 123 mg of migalastat free base.

[0028] In one or more embodiments, the salt of migalastat is migalastat hydrochloride.

[0029] In one or more embodiments, the effective amount is about 150 mg of migalastat hydrochloride.

[0030] In one or more embodiments, the migalastat or a salt thereof is in an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, a capsule, or a solution.

[0031] In one or more embodiments, migalastat or a salt thereof is administered for at least 28 days.

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

[0033] In one or more embodiments, the migalastat or a salt thereof is administered for at least 12 months.

[0034] Another aspect of the invention relates to the use of migalastat to stabilize renal function in a patient diagnosed with Fabry disease and having impaired renal function. In various embodiments, the method comprises administering to the patient about 100 mg to about 150 mg FBE of migalastat or a salt thereof once every other day.

[0035] In one or more embodiments, the patient has mild or moderate renal impairment.

[0036] In one or more embodiments, the patient has mild renal impairment.

[0037] In one or more embodiments, the patient has moderate renal impairment.

[0038] In one or more embodiments, the patient has severe renal impairment.

[0039] In one or more embodiments, the patient is an ERT-experienced patient.

[0040] In one or more embodiments, the patient is an ERT-naive patient.

[0041] In one or more embodiments, the patient has a proteinuria level of less than 100 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0042] In one or more embodiments, the patient has a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0043] In one or more embodiments, the patient has a proteinuria level greater than 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0044] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0045] In one or more embodiments, the effective amount is about 123 mg FBE.

[0046] In one or more embodiments, the effective amount is about 123 mg of migalastat free base.

[0047] In one or more embodiments, the salt of migalastat is migalastat hydrochloride.

[0048] In one or more embodiments, the effective amount is about 150 mg of migalastat hydrochloride.

[0049] In one or more embodiments, the migalastat or a salt thereof is in an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, a capsule, or a solution.

[0050] In one or more embodiments, migalastat or a salt thereof is administered for at least 28 days.

[0051] In one or more embodiments, the migalastat or a salt thereof is administered for at least six months.

[0052] In one or more embodiments, the migalastat or a salt thereof is administered for at least 12 months.

[0053] In one or more embodiments, the administration of an effective amount of migalastat or a salt thereof to a patient population with mild or moderate renal impairment is at a blood flow rate of −1.0 mL / min / 1.73 m 2 Greater eGFR CKD-EPI yielding an average annual rate of change of

[0054] In one or more embodiments, the administration of an effective amount of migalastat or a salt thereof to a patient population with mild renal impairment is at a blood flow rate of −1.0 mL / min / 1.73 m 2 Greater eGFR CKD-EPI yielding an average annual rate of change of

[0055] In one or more embodiments, the administration of an effective amount of migalastat or a salt thereof to a patient population with moderate renal impairment is at a blood glucose level of -1.0 mL / min / 1.73 m 2 Greater eGFR CKD-EPI yielding an average annual rate of change of

[0056] Another aspect of the invention relates to the use of migalastat to stabilize plasma lyso-Gb3 in patients diagnosed with Fabry disease and with impaired renal function. In various embodiments, the method comprises administering to the patient about 100 mg to about 150 mg FBE of migalastat or a salt thereof once every other day.

[0057] In one or more embodiments, the patient has mild or moderate renal impairment.

[0058] In one or more embodiments, the patient has mild renal impairment.

[0059] In one or more embodiments, the patient has moderate renal impairment.

[0060] In one or more embodiments, the patient has severe renal impairment.

[0061] In one or more embodiments, the patient is an ERT-experienced patient.

[0062] In one or more embodiments, the patient is an ERT-naive patient.

[0063] In one or more embodiments, the patient has a proteinuria level of less than 100 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0064] In one or more embodiments, the patient has a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0065] In one or more embodiments, the patient has a proteinuria level greater than 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0066] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0067] In one or more embodiments, the effective amount is about 123 mg FBE.

[0068] In one or more embodiments, the effective amount is about 123 mg of migalastat free base.

[0069] In one or more embodiments, the salt of migalastat is migalastat hydrochloride.

[0070] In one or more embodiments, the effective amount is about 150 mg of migalastat hydrochloride.

[0071] In one or more embodiments, the migalastat or a salt thereof is in an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, a capsule, or a solution.

[0072] In one or more embodiments, migalastat or a salt thereof is administered for at least 28 days.

[0073] In one or more embodiments, the migalastat or a salt thereof is administered for at least six months.

[0074] In one or more embodiments, the migalastat or a salt thereof is administered for at least 12 months.

[0075] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a group of ERT-naive patients with moderate renal impairment results in a mean decrease in plasma lyso-Gb3 of at least about 5 nmol / L after 24 months of administration of migalastat or a salt thereof.

[0076] Another aspect of the invention relates to the use of migalastat to reduce LVMi in a patient diagnosed with Fabry disease and with impaired renal function. In various embodiments, the method comprises administering to the patient about 100 mg to about 150 mg FBE of migalastat or a salt thereof once every other day.

[0077] In one or more embodiments, the patient has mild or moderate renal impairment.

[0078] In one or more embodiments, the patient has mild renal impairment.

[0079] In one or more embodiments, the patient has moderate renal impairment.

[0080] In one or more embodiments, the patient has severe renal impairment.

[0081] In one or more embodiments, the patient is an ERT-experienced patient.

[0082] In one or more embodiments, the patient is an ERT-naive patient.

[0083] In one or more embodiments, the patient has a proteinuria level of less than 100 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0084] In one or more embodiments, the patient has a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0085] In one or more embodiments, the patient has a proteinuria level greater than 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0086] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0087] In one or more embodiments, the effective amount is about 123 mg FBE.

[0088] In one or more embodiments, the effective amount is about 123 mg of migalastat free base.

[0089] In one or more embodiments, the salt of migalastat is migalastat hydrochloride.

[0090] In one or more embodiments, the effective amount is about 150 mg of migalastat hydrochloride.

[0091] In one or more embodiments, the migalastat or a salt thereof is in an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, a capsule, or a solution.

[0092] In one or more embodiments, migalastat or a salt thereof is administered for at least 28 days.

[0093] In one or more embodiments, the migalastat or a salt thereof is administered for at least six months.

[0094] In one or more embodiments, the migalastat or a salt thereof is administered for at least 12 months.

[0095] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to an ERT-naive patient population with moderate renal impairment results in a blood glucose level of at least about 2 g / m after 24 months of administration of migalastat or a salt thereof. 2 This results in a mean decrease in LVMi.

[0096] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a population of ERT-experienced patients with moderate renal impairment provides a renal function improvement of at least about 2 g / m after 18 months of administration of migalastat or a salt thereof. 2 This results in a mean decrease in LVMi.

[0097] Another aspect of the invention relates to the use of migalastat to increase WBC α-Gal A activity in patients diagnosed with Fabry disease and with impaired renal function. In various embodiments, the method comprises administering to the patient about 100 mg to about 150 mg FBE of migalastat or a salt thereof once every other day.

[0098] In one or more embodiments, the patient has mild or moderate renal impairment.

[0099] In one or more embodiments, the patient has mild renal impairment.

[0100] In one or more embodiments, the patient has moderate renal impairment.

[0101] In one or more embodiments, the patient has severe renal impairment.

[0102] In one or more embodiments, the patient is an ERT-experienced patient.

[0103] In one or more embodiments, the patient is an ERT-naive patient.

[0104] In one or more embodiments, the patient has a proteinuria level of less than 100 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0105] In one or more embodiments, the patient has a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0106] In one or more embodiments, the patient has a proteinuria level greater than 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0107] In one or more embodiments, the effective amount is about 123 mg FBE.

[0108] In one or more embodiments, the effective amount is about 123 mg of migalastat free base.

[0109] In one or more embodiments, the salt of migalastat is migalastat hydrochloride.

[0110] In one or more embodiments, the effective amount is about 150 mg of migalastat hydrochloride.

[0111] In one or more embodiments, the migalastat or a salt thereof is in an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, a capsule, or a solution.

[0112] In one or more embodiments, migalastat or a salt thereof is administered for at least 28 days.

[0113] In one or more embodiments, the migalastat or a salt thereof is administered for at least six months.

[0114] In one or more embodiments, the migalastat or a salt thereof is administered for at least 12 months.

[0115] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a group of ERT-naive patients with moderate renal impairment results in a mean increase in WBC α-Gal A activity of at least about 1.4 MU / hr / mg after 24 months of administration of migalastat or a salt thereof.

[0116] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a group of ERT-experienced patients with moderate renal impairment results in a mean increase in WBC α-Gal A activity of at least about 1.4 MU / hr / mg after 18 months of administration of migalastat or a salt thereof.

[0117] Another aspect of the invention relates to the use of migalastat to stabilize renal function in a patient diagnosed with Fabry disease and having hyperproteinuria. In various embodiments, the method comprises administering to the patient about 100 mg to about 150 mg FBE of migalastat or a salt thereof once every other day.

[0118] In one or more embodiments, the patient has mild or moderate renal impairment.

[0119] In one or more embodiments, the patient has mild renal impairment.

[0120] In one or more embodiments, the patient has moderate renal impairment.

[0121] In one or more embodiments, the patient has severe renal impairment.

[0122] In one or more embodiments, the patient is an ERT-experienced patient.

[0123] In one or more embodiments, the patient is an ERT-naive patient.

[0124] In one or more embodiments, the patient has a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0125] In one or more embodiments, the patient has a proteinuria level greater than 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0126] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0127] In one or more embodiments, the effective amount is about 123 mg FBE.

[0128] In one or more embodiments, the effective amount is about 123 mg of migalastat free base.

[0129] In one or more embodiments, the salt of migalastat is migalastat hydrochloride.

[0130] In one or more embodiments, the effective amount is about 150 mg of migalastat hydrochloride.

[0131] In one or more embodiments, the migalastat or a salt thereof is in an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, a capsule, or a solution.

[0132] In one or more embodiments, migalastat or a salt thereof is administered for at least 28 days.

[0133] In one or more embodiments, the migalastat or a salt thereof is administered for at least six months.

[0134] In one or more embodiments, the migalastat or a salt thereof is administered for at least 12 months.

[0135] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a patient group having a proteinuria level of 100 to 1,000 mg / 24 hr before the start of administration of migalastat or a salt thereof results in an increase in eGFR of greater than -2.0 mL / min / 1.73 m2. CKD-EPI yielding an average annual rate of change of

[0136] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a patient group having a proteinuria level of greater than 1,000 mg / 24 hr before initiation of administration of migalastat or a salt thereof results in a proteinuria of -5.0 mL / min / 1.73 m 2 Greater eGFRCKD-EPI yielding an average annual rate of change of

[0137] Another aspect of the invention relates to a method for treating Fabry disease in a patient with hyperproteinuria, comprising administering to the patient an effective amount of migalastat or a salt thereof once every other day. In one or more embodiments, the effective amount is about 100 mg to about 150 mg FBE.

[0138] In one or more embodiments, the patient has mild or moderate renal impairment.

[0139] In one or more embodiments, the patient has mild renal impairment.

[0140] In one or more embodiments, the patient has moderate renal impairment.

[0141] In one or more embodiments, the patient has severe renal impairment.

[0142] In one or more embodiments, the patient is an ERT-experienced patient.

[0143] In one or more embodiments, the patient is an ERT-naive patient.

[0144] In one or more embodiments, the patient has a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0145] In one or more embodiments, the patient has a proteinuria level greater than 1,000 mg / 24 hr prior to initiating administration of migalastat or a salt thereof.

[0146] In one or more embodiments, migalastat or a salt thereof enhances α-Gal A activity.

[0147] In one or more embodiments, the effective amount is about 123 mg FBE.

[0148] In one or more embodiments, the effective amount is about 123 mg of migalastat free base.

[0149] In one or more embodiments, the salt of migalastat is migalastat hydrochloride.

[0150] In one or more embodiments, the effective amount is about 150 mg of migalastat hydrochloride.

[0151] In one or more embodiments, the migalastat or a salt thereof is in an oral dosage form. In one or more embodiments, the oral dosage form comprises a tablet, a capsule, or a solution.

[0152] In one or more embodiments, migalastat or a salt thereof is administered for at least 28 days.

[0153] In one or more embodiments, the migalastat or a salt thereof is administered for at least six months.

[0154] In one or more embodiments, the migalastat or a salt thereof is administered for at least 12 months.

[0155] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a patient group having a proteinuria level of 100 to 1,000 mg / 24 hr before the start of administration of migalastat or a salt thereof results in a proteinuria rate of -2.0 mL / min / 1.73 m 2 Greater eGFR CKD-EPI yielding an average annual rate of change of

[0156] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a patient group having a proteinuria level of greater than 1,000 mg / 24 hr before initiation of administration of migalastat or a salt thereof results in a proteinuria of -5.0 mL / min / 1.73 m 2 Greater eGFR CKD-EPI yielding an average annual rate of change of

[0157] Various embodiments are listed below. It will be understood that the embodiments listed below are not limited to those listed below and may be combined in other suitable combinations within the scope of the present invention. [Brief explanation of the drawings]

[0158] [Figure 1A] Figure 1 shows migalastat plasma concentrations as a function of CLCR for non-Fabry patients with various degrees of renal impairment; [Figure 1B-1C] B shows migalastat plasma concentrations as a function of time after administration for non-Fabry patients with various degrees of renal impairment; C shows the area under the curve (AUC) for non-Fabry patients with various degrees of renal impairment; [Figure 2] Figure 1 shows migalastat concentrations as a function of time for patients with moderate to severe renal impairment; [Figure 3] Correlation between AUC0-∞ and migalastat concentrations at 48 hours for non-Fabry patients with various degrees of renal impairment; [Figure 4] Plasma migalastat concentrations after 48 hours as a function of eGFRMDRD for non-Fabry patients with various degrees of renal impairment and two Fabry patients with renal impairment; [Figure 5] Plasma AUC0-∞ for non-Fabry patients with varying degrees of renal impairment and two Fabry patients with renal impairment is shown; [Figures 6A-6D] Simulated median and observed migalastat concentrations over time for normal, severe, mild, and moderately impaired renal subjects, respectively; [Figures 7A-7D] Simulated Cmax, AUC, Cmin and C48 are shown for normal, mild, moderate and severe renal impairment subjects, respectively; [Figures 8A-8D] Shown are steady-state predictions of QOD for normal, severe, mild and moderate renal impairment subjects, respectively; [Figures 9A-9D]Cmax, AUC, Cmin and C48 are shown for normal, mild, moderate and severe renal impairment subjects, respectively; [Figure 10A] presents the study designs of two trials examining the use of migalastat in Fabry patients; [Figure 10B] presents the study designs of two trials examining the use of migalastat in Fabry patients; [Figure 11] Shows the annual rate of change in eGFRCKD-EPI for Fabry patients receiving migalastat therapy with normal renal function and mild and moderate renal impairment; [Figures 12A-12B] Shown are the annual percentage changes in eGFRCKD-EPI and mGFR iohexol for Fabry patients on migalastat therapy and ERT with normal and impaired renal function, respectively; [Figure 13] Shows the annual percentage change in eGFRCKD-EPI for Fabry patients receiving migalastat therapy and ERT with normal renal function and mild and moderate renal impairment; [Figures 14A-14E] The complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1) is shown; and [Figure 15] The wild-type GLA protein (SEQ ID NO: 2) is shown. DETAILED DESCRIPTION OF THE INVENTION

[0159] Before describing several exemplary embodiments of the invention, it is to be understood that the invention is not limited to the details of construction or method steps set forth in the following description. The invention is capable of other embodiments and of being practiced or carried out in various ways.

[0160] It has been unexpectedly discovered that migalastat therapy stabilizes renal function, reduces LVMi, reduces plasma lyso-Gb3, and increases WBC α-Gal A activity in Fabry patients with mild and moderate renal impairment. Accordingly, various aspects of the present invention relate to specific migalastat dosing regimens for Fabry patients with renal impairment. Migalastat is a pharmacological chaperone used to treat Fabry disease. This pharmacological chaperone is normally cleared from the body by the kidneys. However, patients with renal impairment (a common problem in Fabry patients) may be unable to clear migalastat from the body, and it has previously been unknown how patients with both Fabry disease and renal impairment may respond to migalastat therapy. Because pharmacological chaperones are also inhibitors, it is extremely difficult for pharmacological chaperones such as migalastat to balance enzyme-enhancing and inhibitory effects. Furthermore, due to the complex interactions between Fabry disease and renal function and the lack of knowledge regarding the role of pharmacological chaperones, dosing of migalastat in Fabry patients with renal impairment is difficult to ascertain without valid clinical data and / or computer modeling.

[0161] Accordingly, aspects of the present invention relate to methods of treating Fabry patients with impaired renal function and / or hyperproteinuria using migalastat or a salt thereof, such as by stabilizing the patient's renal function, reducing LVMi, reducing plasma lyso-Gb3, and / or increasing α-Gal A activity.

[0162] In one or more embodiments, the method comprises administering to a patient about 100 mg to about 150 mg FBE of migalastat or a salt thereof once every other day. The patient may have mild, moderate, or severe renal impairment. In one or more embodiments, the patient has mild or moderate renal impairment. In a specific embodiment, the patient has mild renal impairment. In another specific embodiment, the patient has moderate renal impairment.

[0163] definition The terms used herein generally have their ordinary meaning in the art, within the context of this invention and in the specific context in which each term is used. Certain terms are discussed below or elsewhere in this specification to provide further guidance to the practitioner in describing the compositions and methods of the invention and how to make and use them.

[0164] The term "Fabry disease" refers to an X-linked congenital abnormality of glycosphingolipid catabolism resulting from deficient lysosomal α-Gal A activity. This defect leads to the accumulation of the substrate globotriaosylceramide ("GL-3," also known as Gb3 or ceramide trihexoside) and related glycosphingolipids in vascular endothelial lysosomes in the heart, kidney, skin, and other tissues. Another substrate for this enzyme is plasma globotriaosylsphingosine ("plasma lyso-Gb3").

[0165] A "carrier" is a female in whom one X chromosome contains a defective α-Gal A gene and one X chromosome contains a normal gene, and in which there is X chromosome inactivation of the normal allele in one or more cell types. Carriers are often diagnosed with Fabry disease.

[0166] "Patient" refers to a subject who has been diagnosed with or is suspected of having a particular disease. The patient may be a human or an animal.

[0167] "Fabry patient" refers to an individual with mutant α-Gal A, as further defined below, who has been diagnosed with or is suspected of having Fabry disease. The hallmark markers for Fabry disease can occur with equal prevalence in hemizygous male and female carriers, although females are typically affected with less severe disease.

[0168] The term "ERT-naive patient" refers to a Fabry patient who has never received ERT or who has not received ERT for at least 6 months prior to initiating migalastat therapy.

[0169] The term "ERT-experienced patient" refers to a Fabry patient who was receiving ERT immediately prior to initiating migalastat therapy. In some embodiments, an ERT-experienced patient received ERT for at least 12 months immediately prior to initiating migalastat therapy.

[0170] Human α-galactosidase A (α-Gal A) refers to the enzyme encoded by the human GLA gene. The complete DNA sequence of α-Gal A, including introns and exons, is available under GenBank accession number X14448.1 and is shown in SEQ ID NO: 1 and Figures 14A-14E. The human α-Gal A enzyme consists of 429 amino acids and is available under GenBank accession numbers X14448.1 and U78027.1, and is shown in SEQ ID NO: 2 and Figure 15.

[0171] The term "mutant protein" includes proteins that have a mutation in the gene encoding the protein that prevents the protein from achieving a stable conformation under conditions normally present in the ER. Failure to achieve a stable conformation results in significant amounts of the enzyme not being transported to lysosomes but rather being degraded. Such mutations are sometimes referred to as "conformational mutants." Such mutations include, but are not limited to, missense mutations and small in-frame deletions and insertions.

[0172] As used herein in one embodiment, the term "mutant α-Gal A" includes α-Gal A with a mutation in the gene encoding α-Gal A that prevents the enzyme from achieving a stable conformation under conditions normally present in the ER. The inability to achieve a stable conformation results in significant amounts of the enzyme not being transported to lysosomes but rather being degraded.

[0173] As used herein, the term "specific pharmacological chaperone" ("SPC") or "pharmacological chaperone" ("PC") refers to any molecule, including small molecules, proteins, peptides, nucleic acids, carbohydrates, etc., that specifically binds to a protein and has one or more of the following effects: (i) promoting the formation of a stable molecular conformation of the protein; (ii) directing trafficking of the protein from the ER to another cellular site, preferably the native cellular site, i.e., preventing ER-associated degradation of the protein; (iii) preventing aggregation of misfolded proteins; and / or (iv) restoring or enhancing at least some wild-type function and / or activity to a protein. For example, a compound that specifically binds to α-Gal A means that it binds to and exerts a chaperone effect on that enzyme and not on a general group of related or unrelated enzymes. More specifically, the term does not refer to endogenous chaperones such as BiP, or nonspecific agents, i.e., chemical chaperones, that demonstrate nonspecific chaperone activity for a variety of proteins, such as glycerol, DMSO, or heavy water. In one or more embodiments of the invention, the PC may be a reversible competitive inhibitor.

[0174] A "competitive inhibitor" of an enzyme can refer to a compound that is structurally similar to the chemical and molecular structure of the enzyme substrate and binds to the enzyme at approximately the same location as the substrate. Thus, the inhibitor competes for the same active site as the substrate molecule, thus increasing the Km. Competitive inhibition is usually reversible if enough substrate molecules are available to displace the inhibitor; i.e., competitive inhibitors can bind reversibly. Therefore, the amount of enzyme inhibition depends on the inhibitor concentration, the substrate concentration, and the relative affinities of the inhibitor and substrate for the active site.

[0175] As used herein, the term "specifically binds" refers to the interaction of a pharmacological chaperone with a protein, such as α-Gal A, specifically with amino acid residues in the protein that are directly involved in contact with the pharmacological chaperone. A pharmacological chaperone specifically binds to a target protein, e.g., α-Gal A, and exerts a chaperone effect on that protein, rather than on a general group of related or unrelated proteins. The amino acid residues in a protein that interact with a given pharmacological chaperone may or may not be within the "active site" of the protein. Specific binding can be assessed by routine binding assays or by structural studies, e.g., cocrystallization, NMR, etc. The active site of α-Gal A is the substrate-binding site.

[0176] "Deficient α-Gal A activity" refers to α-Gal A activity in cells from a patient that is below the normal range when compared (using the same method) with the activity of normal individuals who do not have or are not suspected of having Fabry disease or any other disease (particularly a hematological disorder).

[0177] As used herein, the terms "enhancing α-Gal A activity" or "increasing α-Gal A activity" refer to increasing the amount of α-Gal A in a stable conformation in cells contacted with an α-Gal A-specific pharmacological chaperone compared to the amount in cells (preferably of the same cell type, or the same cells, e.g., at an earlier stage) that have not been contacted with the α-Gal A-specific pharmacological chaperone. The terms also refer to increasing α-Gal A trafficking to lysosomes in cells contacted with an α-Gal A-specific pharmacological chaperone compared to trafficking of α-Gal A not contacted with a pharmacological chaperone specific for that protein. These terms refer to both wild-type and mutant α-Gal A. In one embodiment, the increase in α-Gal A amount in cells is measured by measuring the hydrolysis of an artificial substrate in lysates from cells treated with PC. Increased hydrolysis is an indication of increased α-Gal A activity.

[0178] The term "α-Gal A activity" refers to the normal physiological function of wild-type α-Gal A in a cell. For example, α-Gal A activity includes the hydrolysis of GL-3.

[0179] A "responder" is an individual diagnosed with or suspected of having a lysosomal storage disorder, e.g., Fabry disease, whose cells respond to contact with PC by exhibiting a sufficient increase in α-Gal A activity and / or alleviation of symptoms or enhancement of a surrogate marker, respectively. Non-limiting examples of enhanced Fabry surrogate markers include lyso-Gb3 and those disclosed in U.S. Patent Application Publication No. 2010 / 0113517, hereby incorporated by reference in its entirety.

[0180] Non-limiting examples of improvements in surrogate markers of Fabry disease disclosed in U.S. Patent Application Publication No. 2010 / 0113517 include increased α-Gal A levels or activity in cells (e.g., fibroblasts) and tissues; decreased GL-3 accumulation; decreased plasma concentrations of homocysteine ​​and vascular cell adhesion molecule-1 (VCAM-1); decreased GL-3 accumulation in cardiomyocytes and valvular fibrocytes; decreased plasma lyso-Gb3; reduced cardiac hypertrophy (especially the left ventricle), valvular insufficiency, and arrhythmias; reduced proteinuria; decreased urinary concentrations of lipids such as CTH, lactosylceramide, and ceramide, and increased urinary concentrations of glucosylceramide and sphingomyelin; absence of lamellar inclusions (zebra bodies) in glomerular epithelial cells; improved renal function; reduced hypohidrosis; absence of angiokeratoma; and improvement in hearing abnormalities such as high-frequency sensorineural hearing loss, progressive hearing loss, sudden hearing loss, or tinnitus. Improvement of neurological symptoms includes prevention of transient ischemic attacks (TIA) or stroke; and reduction of neuropathic pain manifested as acroparesthesia (burning or tingling pain in the extremities). Another clinical marker that may determine Fabry disease is the prevalence of adverse cardiovascular symptoms. Common cardiac signs and symptoms in Fabry disease include left ventricular hypertrophy, valvular disease (especially mitral valve prolapse and / or regurgitation), premature coronary artery disease, angina, myocardial infarction, conduction abnormalities, arrhythmias, and congestive heart failure.

[0181] As used herein, the phrase "stabilization of renal function" and similar terms refer, among other things, to the arrest of deterioration of renal function and / or the restoration of renal function. Because untreated Fabry patients are expected to have significantly reduced renal function, an improvement in the rate of renal deterioration and / or improvement in renal function demonstrates the benefit of migalastat therapy as described herein. Specifically, stabilization of renal function may occur in Fabry patients, regardless of the severity of renal function and whether ERT-naive or ERT-experienced, when compared to similar patients not treated with the therapies of the present invention, e.g., a stabilization of renal function of 0.2 mL / min / 1.73 m for a particular patient population. 2 This can manifest as a significant improvement in renal function or a slowing of the rate of renal function deterioration. An advantage of the treatment methods disclosed herein compared to no treatment (no chaperone or ERT treatment) or ERT treatment is that Fabry patients treated with the methods exhibit little or no deterioration in their renal function. For example, while initial improvement with ERT treatment may be observed, after the first two or three years of therapy, ERT-treated patients experience a rapid deterioration in renal function—similar to the deterioration observed before ERT treatment. In contrast, the therapies described herein have been shown to more efficiently remove lysosomal GL-3, resulting in improvement in patients not expected to improve, e.g., ERT-experienced patients (see, e.g., Example 5). Current clinical data using the therapies described herein are expected to result in continued improvement in patient outcomes even two years after treatment. Accordingly, in some embodiments, patients treated with the therapies described herein continue to experience stable renal function (e.g., due to an improvement in the patient's glomerular filtration rate (GFR) or a slowing of the rate of deterioration in GFR) for more than two years after treatment.

[0182] Renal dysfunction is defined as a GFR of 90 mL / min / 1.73 m 2 Two of the most commonly used formulas for calculating estimated glomerular filtration rate (eGFR) from serum creatinine are: CKD-EPI and eGFR MDRDThese include the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD). The severity of chronic kidney disease is defined in six stages: a. (Stage 0) Normal kidney function - GFR 90 mL / min / 1.73 m 2 above 100°C and no proteinuria; b. (Stage 1) - GFR is 90 mL / min / 1.73 m 2 above 50 and there is evidence of kidney damage; c. (Stage 2) (Mild) - GFR is 60-89 mL / min / 1.73 m 2 and there is evidence of kidney damage; d. (Stage 3) (Moderate) - GFR is 30-59 mL / min / 1.73 m 2 is; e. (Stage 4) (Severe) - GFR is 15-29 mL / min / 1.73 m 2 is; f. (Stage 5) Renal failure - GFR is 15 mL / min / 1.73 m 2 is less than.

[0183] "High proteinuria" refers to a urinary protein level above the normal range. The normal range for urinary protein is 0 to 150 mg per day, so high proteinuria is a urinary protein level of approximately 150 mg per day.

[0184] As used herein, the phrase "stabilizing plasma lyso-Gb3" and similar terms refer to preventing an increase in plasma lyso-Gb3 and / or reducing plasma lyso-Gb3. Because untreated Fabry patients are expected to have significantly increased plasma lyso-Gb3, an improvement in the rate of plasma lyso-Gb3 accumulation and / or an improvement in plasma lyso-Gb3 demonstrates the benefit of migalastat therapy as described herein.

[0185] A dose that achieves one or more of the aforementioned responses is a "therapeutically effective dose."

[0186] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and typically do not produce adverse reactions when administered to humans. In some embodiments, as used herein, the term "pharmaceutically acceptable" means approved by a federal or state regulatory agency for use in animals, more particularly in humans, or listed in the United States Pharmacopeia or other generally recognized pharmacopeia. With respect to pharmaceutical carriers, the term "carrier" refers to a diluent, adjuvant, excipient, or vehicle with which a compound is administered. Such pharmaceutical carriers may be sterile liquids, such as water and oils. Water or aqueous solutions, saline solutions, and aqueous dextrose and glycerol solutions are preferably utilized as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin, 18th Edition, or other editions.

[0187] The term "enzyme replacement therapy" or "ERT" refers to the introduction of a non-native purified enzyme into an individual deficient in such an enzyme. The administered protein may be obtained from a natural source or by recombinant expression (as described in more detail below). The term also refers to the introduction of a purified enzyme in an individual who would otherwise require or benefit from the administration of the purified enzyme, e.g., an individual suffering from an enzyme deficiency. The introduced enzyme may be a purified recombinant enzyme made in vitro, or may be a protein purified from isolated tissue or body fluids, such as placenta or animal milk, or purified from a plant.

[0188] As used herein, the term "isolated" means that the referenced material is removed from the environment in which it is normally found. Thus, isolated biological material can be free of cellular components, i.e., components of the cells in which the material is found or produced. In the case of nucleic acid molecules, isolated nucleic acids include PCR products, mRNA bands on gels, cDNA, or restriction fragments. In another embodiment, isolated nucleic acids are preferably excised from the chromosome in which they are found, and more preferably, when found in a chromosome, they are no longer connected to non-regulatory regions, non-coding regions, or other genes located upstream or downstream of the gene contained in the isolated nucleic acid molecule. In yet another embodiment, isolated nucleic acids lack one or more introns. Isolated nucleic acids include sequences inserted into plasmids, cosmids, artificial chromosomes, etc. Thus, in a specific embodiment, recombinant nucleic acids are isolated nucleic acids. An isolated protein may be associated with other proteins or nucleic acids, or both, with the cell to which it is associated, or, if it is a membrane-bound protein, with the cell membrane. An isolated organelle, cell, or tissue is removed from the anatomical site in an organism in which it is found. An isolated material may, but need not, be purified.

[0189] The terms "about" and "approximately" are generally intended to refer to an acceptable degree of error for the measured quantity, given the nature or precision of the measurement. Typical exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Alternatively, particularly in biological systems, the terms "about" and "approximately" can refer to values ​​within an order of magnitude of a given value, preferably within 10-fold or 5-fold, and more preferably within 2-fold. Numerical quantities provided herein are approximate unless otherwise specified, i.e., the terms "about" or "approximately" can be implied even when not explicitly stated.

[0190] As used herein, the term "free base equivalent" or "FBE" refers to the amount of migalastat present in migalastat or a salt thereof. In other words, the term "FBE" refers to either the amount of migalastat free base or the equivalent amount of migalastat free base provided by a salt of migalastat. For example, due to the weight of the hydrochloride salt, only 150 mg of migalastat hydrochloride provides the same amount of migalastat as 123 mg of migalastat in free base form. Other salts are expected to have different conversion factors depending on the molecular weight of the salt.

[0191] The term "migalastat" includes migalastat free base or a pharmaceutically acceptable salt thereof (eg, migalastat HCl), unless specifically indicated to the contrary.

[0192] Fabry disease Fabry disease is a rare, progressive, severe, X-linked lysosomal storage disorder. Mutations in the GLA gene cause a deficiency of the lysosomal enzyme α-Gal A, which is required for glycosphingolipid metabolism. Decreased α-Gal A activity, which begins in early childhood, leads to the accumulation of glycosphingolipids, including GL-3 and plasma lyso-Gb3, leading to the symptoms and fatal sequelae of Fabry disease, including pain, gastrointestinal symptoms, renal failure, cardiomyopathy, cerebrovascular events, and premature death. Early initiation of therapy and lifelong treatment offers the opportunity to slow disease progression and extend life expectancy.

[0193] Fabry disease encompasses a range of disease severity and age of onset, but is traditionally divided into two major phenotypes, "classic" and "late-onset." The classic phenotype is primarily considered to be in men with undetectable to low α-Gal A activity and early onset of renal, cardiac, and / or cerebrovascular symptoms. The late-onset phenotype is primarily considered to be in men with higher residual α-Gal A activity and later onset of these disease symptoms. Heterozygous female carriers typically express the late-onset phenotype, but may also exhibit the classic phenotype depending on the pattern of X-chromosome inactivation.

[0194] Over 800 GLA mutations responsible for Fabry disease have been identified. Approximately 60% are missense mutations resulting in a single amino acid substitution in the α-Gal A enzyme. Missense GLA mutations often result in the production of abnormally folded, unstable forms of α-Gal A, the majority of which are associated with the classic phenotype. Normal cellular quality control mechanisms in the endoplasmic reticulum prevent these abnormal proteins from trafficking to lysosomes, targeting them for premature degradation and removal. Many missense mutant forms are targets of migalastat, an α-Gal A-specific pharmacological chaperone.

[0195] The clinical manifestations of Fabry disease range in severity and roughly correlate with a patient's residual α-GAL levels. The majority of patients currently receiving treatment are referred to as patients with classic Fabry disease, most of whom are men. These patients experience disease in various organs, including the kidneys, heart, and brain. Disease symptoms first appear in adolescence and progress in severity until death, typically in the patient's 30s or 40s. Several recent studies suggest that there are many undiagnosed men and women with various Fabry disease symptoms, such as cardiac or renal dysfunction and stroke, that usually first appear in adulthood. This type of Fabry disease, referred to as late-onset Fabry disease, tends to have higher residual α-GAL levels than patients with classic Fabry disease. Late-onset Fabry disease patients typically experience their first disease symptoms in adulthood and often have disease symptoms localized to a single organ, such as left ventricular hypertrophy or progressive renal failure. In addition, late-onset Fabry disease can also present as stroke of unknown etiology.

[0196] Patients with Fabry disease have progressive renal dysfunction, and untreated individuals develop end-stage renal failure by their fourth decade. Deficiency of α-Gal A activity leads to the accumulation of GL-3 and related glycosphingolipids in many cell types, including those of the kidney. GL-3 accumulates in podocytes, distal tubules, and epithelial and tubular cells of the loop of Henle. Renal dysfunction can manifest as proteinuria and a reduced glomerular filtration rate.

[0197] Because Fabry disease can cause progressive deterioration of renal function, it is important to understand the pharmacokinetics (PK) of potential therapeutic agents in renal impairment, especially for agents that are primarily eliminated by renal excretion. Impaired renal function can lead to the accumulation of therapeutic agents to toxic levels.

[0198] Proper diagnosis of Fabry disease is challenging due to its rarity, multiorgan involvement, wide age range of onset, and heterogeneity. Misdiagnosis is frequent due to low awareness among medical professionals. The diagnosis of Fabry disease is most often confirmed after a patient presents with symptoms, based on reduced α-Gal A activity in plasma or peripheral white blood cells (WBCs) in conjunction with mutation analysis. Diagnosis is even more challenging in females, due to unreliable enzymatic identification of carrier females due to random X-chromosome inactivation in some carrier cells. For example, some obligate carriers (daughters of classically affected men) have α-Gal A enzyme activity ranging from normal to very low activity. Because carriers may have normal α-Gal A enzyme activity in white blood cells, only identification of the α-Gal A mutation by genetic testing provides accurate carrier identification and / or diagnosis.

[0199] A mutant form of α-galactosidase A that is considered migalastat applicable is defined as one that exhibits a ≥ 1.20-fold relative increase (+10 μM migalastat) over wild-type and a ≥ 3.0% absolute increase (+10 μM migalastat) when the mutant form of α-galactosidase A is expressed in HEK-293 cells according to a Good Laboratory Practice (GLP) validated in vitro assay (GLP HEK or migalastat applicability assay) (referred to as the "HEK assay"). Such mutations are also referred to herein as "HEK assay applicable" mutations.

[0200] Prior screening methods have been provided to determine enzyme enhancement before treatment begins. For example, an assay using HEK-293 cells has been utilized in clinical trials to predict whether a given mutation will respond to pharmacological chaperone (e.g., migalastat) treatment. In this assay, a cDNA construct is generated. The corresponding α-Gal A mutant form is transiently expressed in HEK-293 cells. The cells are then incubated with migalastat (17 nM to 1 mM) for 4 to 5 days. α-Gal A levels are then measured in cell lysates using a synthetic fluorogenic substrate (4-MU-α-Gal) or by Western blot. This has been performed for known disease-causing missense or small in-frame insertion / deletion mutations. Mutations previously identified as responsive to PC (e.g., migalastat) using these methods are listed in U.S. Patent No. 8,592,362 (hereby incorporated by reference in their entirety).

[0201] Pharmacological Chaperones Binding of small molecule inhibitors of LSD-related enzymes can increase the stability of both mutant and corresponding wild-type enzymes (see U.S. Patent Nos. 6,274,597; 6,583,158; 6,589,964; 6,599,919; 6,916,829; and 7,141,582, all of which are incorporated herein by reference). Specifically, administration of small molecule derivatives of glucose and galactose, which are specific and selective competitive inhibitors of several target lysosomal enzymes, effectively increased the stability of the enzymes in cells in vitro, thereby increasing the trafficking of the enzymes to lysosomes. Therefore, increasing the amount of enzymes in lysosomes is expected to increase the hydrolysis of the enzyme substrates. The original theory behind this strategy was as follows: Because mutant enzyme proteins are unstable in the ER (Ishii et al., Biochem. Biophys. Res. Comm. 1996;220:812-815), they are delayed in their normal transport pathway (ER → Golgi apparatus → endosomes → lysosomes) and are prematurely degraded. Therefore, compounds that bind to and increase the stability of mutant enzymes could act as "chaperones" for the enzymes, increasing the amount that can exit the ER and be transported to lysosomes. In addition, because folding and trafficking of some wild-type proteins are incomplete, and in some cases up to 70% of some wild-type proteins are degraded before reaching their final cellular location, chaperones could be used to stabilize wild-type enzymes, increasing the amount of enzyme that can exit the ER and be transported to lysosomes.

[0202] In one or more embodiments, the pharmacological chaperone comprises migalastat or a salt thereof. The compound migalastat, also known as 1-deoxygalactonojirimycin (1-DGJ) or (2R,3S,4R,5S)-2-(hydroxymethyl)piperdine-3,4,5-triol, is a compound having the following chemical formula: TIFF2025143262000002.tif59170

[0203] As discussed herein, pharmaceutically acceptable salts of migalastat may also be used in the present invention. When a salt of migalastat is used, the dosage of the salt will be adjusted so that the patient receives a dose of migalastat equivalent to the amount that they would have received if migalastat free base had been used. An example of a pharmaceutically acceptable salt of migalastat is migalastat HCl: TIFF2025143262000003.tif59170

[0204] Migalastat is a low-molecular-weight iminosugar and an analog of the terminal galactose of GL-3. In vitro and in vivo pharmacological studies have demonstrated that migalastat acts as a pharmacological chaperone, binding with high affinity, selectivity, and reversibility to the active site of wild-type α-Gal A and specific mutant forms of α-Gal A (these genotypes are referred to as HEK assay-compatible mutations). Upon binding, migalastat stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum, promoting their proper trafficking to lysosomes, where its dissociation allows α-Gal A to reduce levels of GL-3 and other substrates. Approximately 30-50% of patients with Fabry disease have HEK assay-compatible mutations; the majority of these are associated with the classic phenotype of the disease. The list of HEK assay-compatible mutations includes at least those listed in Table 1 below. In one or more embodiments, when double mutations are present on the same chromosome (male and female), the patient is considered eligible for the HEK assay if the double mutations are present in one entry in Table 1 (e.g., D55V / Q57L). In some embodiments, when double mutations are present on different chromosomes (females only), the patient is considered eligible for the HEK assay if either of the individual mutations are present in Table 1. In addition to Table 1 below, HEK assay eligible mutations can also be found in the GALAFOLD™ Summary of Product Characteristics and / or Prescribing Information in the various countries in which GALAFOLD™ is approved for use, or on the website www.galafoldamenabilitytable.com (each of which is hereby incorporated by reference in its entirety).

[0205] TIFF2025143262000004.tif156170

[0206] TIFF2025143262000005.tif245170

[0207] TIFF2025143262000006.tif248170

[0208] TIFF2025143262000007.tif248170

[0209] TIFF2025143262000008.tif248170

[0210] TIFF2025143262000009.tif248170

[0211] TIFF2025143262000010.tif248170

[0212] TIFF2025143262000011.tif248170

[0213] Renal function in Fabry patients Progressive deterioration of renal function is a major complication of Fabry disease. For example, patients associated with the classic Fabry phenotype present with progressive renal failure that may ultimately require dialysis or kidney transplantation.

[0214] A commonly used method in the art for assessing renal function is GFR. Generally, GFR is the volume of fluid filtered from the renal glomerular capillaries into Bowman's capsule per unit time. In clinical practice, GFR is estimated based on the clearance of creatinine from serum. GFR can be estimated by collecting urine and determining the amount of creatinine removed from the blood over a given time interval. Age, body size, and gender can also be included as factors. The lower the GFR value, the more advanced the kidney damage.

[0215] Some studies have shown that untreated Fabry patients have an average of 7.0 to 18.9 mL / min / 1.73 m per year. 2 patients on ERT experienced a worsening of GFR of 2.0–2.7 mL / min / 1.73 m per year on average. 2It has been noted that patients with ≥ 100% urinary tract infections may experience a worsening of GFR, although more rapid deterioration may occur in patients with more severe proteinuria or more severe chronic kidney disease.

[0216] Estimated GFR (eGFR) is calculated from serum creatinine using an isotope dilution mass spectrometry (IDMS) traceable formula. Two of the most commonly used formulas for estimating glomerular filtration rate (GFR) from serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula and the Modification of Diet in Renal Disease (MDRD) formula. Both the MDRD and CKD-EPI formulas include variables for age, sex, and race, which may allow providers to observe the presence of CKD despite serum creatinine levels appearing to be within or only slightly above the normal reference range.

[0217] The CKD-EPI equation uses two slope "splines" to model the relationship between GFR and serum creatinine, age, sex, and race. The CKD-EPI equation is expressed as a single equation: GFR = 141 × min(S cr / κ,1)α×max(S cr / κ,1)-1.209×0.993 年齢 × 1.018 [for women] × 1.159 [for black people] During the ceremony: S cr is serum creatinine in mg / dL, Kappa is 0.7 for women and 0.9 for men, Alpha was −0.329 for women and −0.411 for men, min is S cr / κ is the minimum value or 1, and max is S cr / κ indicates the maximum value or 1.

[0218] Below is the IDMS traceable MDRD research formula (for the creatinine method calibrated to the IDMS reference method): GFR (mL / min / 1.73m 2 )=175×(S cr ) -1.154 ×(age) -0.203 × (0.742 for women) × (1.212 for African Americans)

[0219] This formula is based on the commonly accepted average adult body surface area of ​​1.73 m 2 Results are reported normalized to body surface area, eliminating the need for weight or height variables. This formula is applicable to patients aged 18 to 70 years with impaired renal function (eGFR < 60 mL / min / 1.73 m). 2 ) It has been well validated in Caucasian and African American populations and has shown good performance in patients with all common causes of kidney disease.

[0220] Creatinine clearance rate (eC Cr One way to estimate GFR is to use the Cockcroft-Gault formula, which in turn estimates GFR in mL / min: Creatinine clearance (mL / min) = [(140 - age) x weight (kg)] * ] ÷ 72 × serum creatinine (mg / dL) [ * For women, multiply by 0.85]

[0221] The Cockcroft-Gault formula is recommended by the Food and Drug Administration for use in studies of renal dysfunction. Creatinine clearance calculated by the Cockcroft-Gault formula is 1.73 m 2 It is common to normalize by body surface area. Therefore, this formula is mL / min / 1.73m 2It can be expressed as an estimated eGFR in units of 1. The normal range for GFR adjusted for body surface area is 100-130 mL / min / 1.73 m² for men younger than 40 years and 90-120 mL / min / 1.73 m² for women.

[0222] The severity of chronic kidney disease is defined into six stages (see also Table 2): (Stage 0) Normal kidney function - GFR 90 mL / min / 1.73 m 2 and no proteinuria; (Stage 1) - GFR 90 mL / min / 1.73 m 2 and evidence of kidney damage; (Stage 2) (Mild) - GFR 60-89 mL / min / 1.73 m 2 and evidence of kidney damage; (Stage 3) (Moderate) - GFR 30-59 mL / min / 1.73 m 2 Stage 4 (Severe) - GFR is 15-29 mL / min / 1.73 m 2 (Stage 5) Renal failure - GFR 15 mL / min / 1.73 m 2 Table 2 below shows the various kidney disease stages with corresponding GFR levels.

[0223] TIFF2025143262000012.tif82170

[0224] Dosing, Formulation and Administration One or more of the dosing regimens described herein are particularly suitable for Fabry patients with some degree of renal impairment. Several studies have investigated the use of 150 mg of migalastat hydrochloride every other day (QOD) in Fabry patients. One study was a 24-month trial with a 6-month double-blind, placebo-controlled period in 67 ERT-naive patients. Another study was an 18-month active-controlled trial in 57 ERT-experienced patients with a 12-month open-label extension (OLE). Both studies included patients with an estimated glomerular filtration rate (eGFR) of ≥ 30 mL / min / 1.73 m 2Thus, both studies included Fabry patients with normal renal function and patients with mild and moderate renal impairment, but neither study included patients with severe renal impairment.

[0225] Studies of migalastat treatment of Fabry patients have established that 150 mg of migalastat hydrochloride every other day slows disease progression as shown by surrogate markers.

[0226] Thus, in one or more embodiments, a Fabry patient is administered migalastat or a salt thereof once every other day (also referred to as "QOD"). In various embodiments, the doses described herein relate to migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt. In some embodiments, these doses relate to the free base of migalastat. In alternative embodiments, these doses relate to a salt of migalastat. In further embodiments, the salt of migalastat is migalastat hydrochloride. The administration of migalastat or a salt of migalastat is referred to herein as "migalastat therapy."

[0227] An effective amount of migalastat or a salt thereof can range from about 100 mg FBE to about 150 mg FBE. Exemplary doses include about 100 mg FBE, about 105 mg FBE, about 110 mg FBE, about 115 mg FBE, about 120 mg FBE, about 123 mg FBE, about 125 mg FBE, about 130 mg FBE, about 135 mg FBE, about 140 mg FBE, about 145 mg FBE, or about 150 mg FBE.

[0228] It is again noted that 150 mg of migalastat hydrochloride is equivalent to 123 mg of the free base form of migalastat. Thus, in one or more embodiments, the dose is 150 mg of migalastat hydrochloride administered once every other day, or an equivalent dose of migalastat or a salt thereof other than the hydrochloride salt. As indicated above, this dose is referred to as 123 mg FBE of migalastat. In a further embodiment, the dose is 150 mg of migalastat hydrochloride administered once every other day. In other embodiments, the dose is 123 mg of migalastat free base administered once every other day.

[0229] In various embodiments, the effective amount is about 122 mg, about 128 mg, about 134 mg, about 140 mg, about 146 mg, about 150 mg, about 152 mg, about 159 mg, about 165 mg, about 171 mg, about 177 mg, or about 183 mg of migalastat hydrochloride.

[0230] Thus, in various embodiments, migalastat therapy comprises administering 150 mg of migalastat hydrochloride every other day, such as 123 mg FBE once every other day.

[0231] Administration of migalastat or a salt thereof can be over a period of time. In one or more embodiments, migalastat or a salt thereof is administered for a duration of at least 28 days, e.g., at least 30, 60, or 90 days, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30, or 36 months, or at least 1, 2, 3, 4, or 5 years. In various embodiments, the migalastat therapy is long-term migalastat therapy for at least 6 months, e.g., at least 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30, or 36 months, or at least 1, 2, 3, 4, or 5 years.

[0232] The administration of migalastat or a salt thereof according to the present invention may be in a formulation suitable for any route of administration, but is preferably administered in an oral dosage form such as a tablet, capsule, or solution. As an example, a patient is orally administered capsules each containing 150 mg of migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof other than hydrochloride.

[0233] In some embodiments, the PC (e.g., migalastat or a salt thereof) is administered orally. In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered by injection. The PC may be accompanied by a pharmaceutically acceptable carrier, which may depend on the method of administration.

[0234] In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered as monotherapy and can be in a form suitable for any route of administration, such as orally in tablet or capsule or liquid form, or in a sterile aqueous solution for injection, etc. In other embodiments, the PC is provided as a lyophilized powder that is added to the replacement enzyme formulation during or immediately after reconstitution to prevent enzyme aggregation in vitro prior to administration.

[0235] When a PC (e.g., migastat or a salt thereof) is formulated for oral administration, tablets or capsules may be prepared by conventional means with pharmaceutically acceptable excipients such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form, for example, of solutions, syrups, or suspensions, or may be prepared as a dry product for constitution with water or another suitable vehicle before use. Such liquid formulations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). The formulations may also contain buffer salts, flavoring agents, coloring agents, and sweetening agents, as appropriate. Formulations for oral administration may be suitably formulated to give controlled release of the active chaperone compound.

[0236] Pharmaceutical formulations of PC (e.g., migastat or its salts) suitable for parenteral / injectable use generally include sterile aqueous solutions (where water soluble), or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, and the like. In many cases, it will be advisable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0237] Sterile injectable solutions are prepared by blending the required amount of purified enzyme (if present) and PC (e.g., migalastat or its salts) in an appropriate solvent with various other ingredients as enumerated above, as needed, followed by filtration or terminal sterilization. Generally, dispersions are prepared by blending the various sterilized active ingredients in a sterile vehicle containing the basic dispersion medium and the other required ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredients from a previously sterile-filtered solution thereof.

[0238] The formulation may contain an excipient. Pharmaceutically acceptable excipients that may be included in the formulation include buffers, such as citrate buffer, phosphate buffer, acetate buffer, bicarbonate buffer, amino acids, urea, alcohols, ascorbic acid, and phospholipids; proteins such as serum albumin, collagen, and gelatin; salts such as EDTA or EGTA, and sodium chloride; liposomes; polyvinylpyrollidone; sugars such as dextran, mannitol, sorbitol, and glycerol; propylene glycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol; glycine or other amino acids; and lipids. Buffer systems used with the formulation include citrate, acetate, bicarbonate, and phosphate buffers. Phosphate buffers are a preferred embodiment.

[0239] The route of administration of the chaperone compound may be oral or parenteral, including intravenous, subcutaneous, intra-arterial, intraperitoneal, intraocular, intramuscular, buccal, rectal, intravaginal, intraorbital, intracerebral, intradermal, intracranial, intraspinal, intraventricular, intrathecal, intracisternal, intravesicular, intrapulmonary, intranasal, transmucosal, transdermal, or by inhalation.

[0240] Administration of the chaperone compound in the parenteral formulations described above may be by periodic injection of a bolus of the formulation, or by intravenous or intraperitoneal administration from an external (e.g., an IV bag) or internal (e.g., a bioerodible implant) reservoir.

[0241] Embodiments relating to pharmaceutical formulations and administration may be combined with any of the other embodiments of the invention, such as methods of treating patients with Fabry disease, methods of treating ERT-naive patients with Fabry disease, methods of reducing renal GL-3, methods of stabilizing renal function, methods of reducing LVM or LVMi, methods of reducing plasma lyso-Gb3 and / or methods of treating gastrointestinal symptoms (e.g., diarrhea), methods of enhancing α-Gal A in patients diagnosed with or suspected of having Fabry disease, embodiments relating to the use of a pharmacological chaperone to α-Gal A for the manufacture of a medicament for the treatment of patients diagnosed with Fabry disease, or embodiments relating to a pharmacological chaperone to α-Gal A for use in the treatment of patients diagnosed with Fabry disease, and embodiments relating to applicable mutations, PCs and suitable dosages thereof.

[0242] In one or more embodiments, the PC (e.g., migalastat or a salt thereof) is administered in combination with ERT. ERT increases the amount of protein by exogenously introducing a wild-type or biologically functional enzyme via infusion. As discussed above, this therapy has been developed for many genetic disorders, including LSDs such as Fabry disease. After infusion, the exogenous enzyme is assumed to be taken up by tissues via nonspecific or receptor-specific mechanisms. Generally, uptake efficiency is not high, and the circulation time of exogenous proteins is short. In addition, exogenous proteins are unstable, subject to rapid intracellular degradation, and there is also the possibility of adverse immune reactions with subsequent treatment. In one or more embodiments, a chaperone is administered simultaneously with the replacement enzyme (e.g., replacement α-Gal A). In some embodiments, the chaperone is formulated with the replacement enzyme (e.g., replacement α-Gal A).

[0243] In one or more embodiments, the patient is switched from ERT to migalastat therapy.In some embodiments, the patient who is receiving ERT is identified, the patient's ERT is discontinued, and the patient begins to receive migalastat therapy.The migalastat therapy can be according to any of the methods described herein.

[0244] Stabilization of renal function The dosing regimens described herein can stabilize renal function in Fabry patients with varying degrees of renal impairment. In one or more embodiments, a Fabry patient with renal impairment is administered about 100 mg to about 150 mg FBE of migalastat or a salt thereof once every other day. In one or more embodiments, the patient is administered 123 mg FBE of migalastat or a salt thereof, such as 123 mg migalastat or 150 mg migalastat hydrochloride, every other day. In one or more embodiments, the patient has mild or moderate renal impairment. In a specific embodiment, the patient has mild renal impairment. In another specific embodiment, the patient has moderate renal impairment. The patient can be ERT-naive or ERT-experienced.

[0245] Administration of migalastat can be over a period of time. In one or more embodiments, migalastat is administered for at least 28 days, e.g., at least 30, 60, or 90 days, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, or 24 months, or at least 1, 2, 3, 4, or 5 years. In various embodiments, the migalastat therapy is long-term migalastat therapy for at least 6 months, e.g., at least 6, 7, 8, 9, 10, 11, 12, 16, 20, or 24 months, or at least 1, 2, 3, 4, or 5 years.

[0246] Migalastat therapy may inhibit the deterioration of renal function in Fabry patients compared to the same patients not treated with migalastat therapy. In one or more embodiments, migalastat therapy may inhibit the deterioration of renal function in Fabry patients compared to the same patients not treated with migalastat therapy. In one or more embodiments, migalastat therapy inhibits ... 2 / year greater than (i.e., positive than), for example, greater than -4.5, -4.0, -3.5, -3.0, -2.5, -2.0, -1.5, -1.0, -0.9, -0.8, -0.7, -0.6, -0.5, -0.4, -0.3, -0.2, -0.1 or even 0 mL / min / 1.73 m 2 eGFR > / year CKD-EPIIn one or more embodiments, migalastat therapy provides a patient with an annual change of -5.0 mL / min / 1.73 m 2 / year, e.g., greater than -4.5, -4.0, -3.5, -3.0, -2.5, -2.0, -1.5, -1.0, -0.9, -0.8, -0.7, -0.6, -0.5, -0.4, -0.3, -0.2, -0.1 or even 0 mL / min / 1.73 m 2 mGFR > / year イオヘキソール The migalastat therapy results in a patient with an annual change of 12, 18, 24, 30, 36, 48, or 60 months. Thus, migalastat therapy may prevent deterioration of, or even improve, a patient's renal function. These annual changes can be measured over a specified period of time, such as over 6, 12, 18, 24, 30, 36, 48, or 60 months.

[0247] Migalastat therapy may slow the deterioration of renal function in certain Fabry patient populations, such as subpopulations of Fabry patients with varying degrees of renal impairment. In one or more embodiments, migalastat therapy may slow the deterioration of renal function in Fabry patients with mild, moderate, or severe renal impairment, resulting in a decrease of -5.0 mL / min / 1.73 m 2 / year, e.g., greater than -4.5, -4.0, -3.5, -3.0, -2.5, -2.0, -1.5, -1.0, -0.9, -0.8, -0.7, -0.6, -0.5, -0.4, -0.3, -0.2, -0.1 or even 0 mL / min / 1.73 m 2 eGFR > / year CKD-EPI In one or more embodiments, migalastat therapy results in a mean annualized change of -5.0 mL / min / 1.73 m in patients with mild, moderate, or severe renal impairment. 2 / year, e.g., greater than -4.5, -4.0, -3.5, -3.0, -2.5, -2.0, -1.5, -1.0, -0.9, -0.8, -0.7, -0.6, -0.5, -0.4, -0.3, -0.2, -0.1 or even 0 mL / min / 1.73 m 2 mGFR > / year イオヘキソールThese annualized rates of change can be measured over a particular period, such as over 6, 12, 18, 24, 30, 36, 48, or 60 months.

[0248] Left ventricular volume The dosing regimens described herein can improve LVMi in Fabry patients. Regardless of phenotype, the natural history of LVMi and cardiac hypertrophy in untreated Fabry patients (Patel, O'Mahony et al. 2015) ranges from +4.07 to +8.0 g / m 2 There is a progressive increase in LVMi per year (Kampmann, Linhart et al. 2008; Wyatt, Henley et al. 2012; Germain, Weidemann et al. 2013). Untreated Fabry patients typically exhibit an increase in LVMi over time, so both a decrease in LVMi and its maintenance are indicators of benefit from migalastat therapy.

[0249] Migalastat therapy may inhibit the increase in LVMi in Fabry patients compared to the same patients without treatment with migalastat therapy. In one or more embodiments, migalastat therapy is administered at a dose of 0 g / m 2 less than (i.e., more negative than), for example, about −0.5, −1, −1.5, −2, −2.5, −3, −3.5, −4, −4.5, −5, −5.5, −6, −7, −8, −9, −10, −11, −12, −13, −14, −15, −16, −17, −18, −19 or −20 g / m 2 Alternatively stated, in one or more embodiments, migalastat therapy results in a change in LVMi of 0 g / m 2 A greater reduction in LVMi, e.g., at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 g / m 2In one or more embodiments, the patient has mild or moderate renal impairment. In a specific embodiment, the patient has mild renal impairment. In another specific embodiment, the patient has moderate renal impairment. The patient can be ERT-naive or ERT-experienced.

[0250] In one or more embodiments, migalastat therapy provides a vasopressin-dependent vasopressin (vasopressin) reduction of at least about 1 g / m2 after 18 months of administration of migalastat or a salt thereof in an ERT-experienced patient population. 2 In various embodiments, the mean reduction in LVMi in the ERT-experienced patient population after 18 months of administration of migalastat or a salt thereof is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g / m 2 is.

[0251] In one or more embodiments, migalastat therapy provides a renal function improvement of at least about 1 g / m after 18 months of administration of migalastat or a salt thereof in an ERT-experienced patient population with moderate renal impairment. 2 In various embodiments, the mean reduction in LVMi in the ERT-experienced patient population after 18 months of administration of migalastat or a salt thereof is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g / m 2 is.

[0252] In one or more embodiments, migalastat therapy provides a vasopressin-dependent vasopressin (vasopressin) reduction of at least about 1 g / m2 after 24 months of administration of migalastat or a salt thereof in an ERT-naive patient population. 2 In various embodiments, the mean reduction in LVMi in ERT-naive patients after 24 months of administration of migalastat or a salt thereof is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g / m 2 is.

[0253] In one or more embodiments, migalastat therapy achieves a renal function improvement of at least about 1 g / m after 24 months of administration of migalastat or a salt thereof in an ERT-naive patient population with moderate renal impairment. 2In various embodiments, the mean reduction in LVMi in ERT-naive patients after 24 months of administration of migalastat or a salt thereof is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g / m 2 is.

[0254] Throughout this specification, the phrases "one embodiment," "particular embodiment," "various embodiments," "one or more embodiments," or "an embodiment" mean that the particular feature, structure, material, or characteristic described in connection with that embodiment is included in at least one embodiment of the invention. Thus, the appearance of phrases such as "in one or more embodiments," "particular embodiment," "various embodiments," "in one embodiment," or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.

[0255] Although the invention herein has been described with reference to detailed embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made in the method and apparatus of the present invention without departing from the spirit and scope of the invention. Therefore, it is intended that the present invention cover such modifications and variations provided they come within the scope of the appended claims and their equivalents.

[0256] Patents, patent applications, publications, product descriptions, and protocols are cited throughout this application, the disclosures of which are incorporated herein by reference in their entirety for all purposes. [Example]

[0257] Example 1: Pharmacokinetics of migalastat in non-Fabry patients with renal impairment A clinical trial was conducted to investigate the pharmacokinetics and safety of migalastat HCl in non-Fabry subjects with renal impairment. Subjects with mild, moderate, and severe renal impairment, as well as normal renal function, were administered a single 150 mg dose of migalastat HCl. eGFR was estimated using the Cockcroft-Gault equation in accordance with FDA guidance for studies of renal impairment.

[0258] Volunteers were asked to measure creatinine clearance (CL CR The subjects were enrolled in two cohorts stratified by renal function calculated using the Cockcroft-Gault formula. CR For each subject, the following plasma migalastat PK parameters were determined by non-compartmental analysis with WinNonlin® software (Pharsight Corporation, version 5.2): C max Highest measured concentration t max Time to reach maximum concentration AUC 0-t Area under the concentration-time curve from time 0 to the last measurable concentration, calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations AUC 0-∞ Area under the concentration-time curve, extrapolated to infinity, calculated using the following formula: AUC0-∞=AUC0-t+Ct / λZ where Ct is the final measurable concentration and λZ is the apparent terminal elimination rate constant. λz apparent terminal elimination rate constant, where λz is the magnitude of the slope of the linear regression of the log concentration versus time profile in the terminal phase t 1 / 2 Apparent terminal elimination half-life (if available), where t 1 / 2 =(ln2) / λZ CL / F Oral clearance calculated as dose / AUC0-∞ Vd / F Oral volume of distribution calculated as dose / AUC0-∞·λZ C 48 48-hour concentration after administration

[0259] The pharmacokinetic parameters to be determined were: AUC (Area under 0-t ) and extrapolated to infinity (AUC 0-∞ ) Area under the concentration-time curve (AUC), maximum observed concentration (C max ), C max Arrival time (t max ), 48-hour concentration after administration (C 48 ), terminal elimination half-life (t 1 / 2 ), oral clearance (CL / F), and apparent terminal elimination rate constant (λz).

[0260] Test subjects had creatinine clearance (CL) as determined using the Cockcroft-Gault formula. CR ) is less than 90 mL / min (i.e., CL CR Renal dysfunction was defined as occurring if the CLcr was <90 mL / min. Subjects were classified according to the degree of renal dysfunction: mild (CLcr ≥ 60 and <90 mL / min), moderate (CL CR ≥30 and <60 mL / min), or severe (CL CR ≥15 and <30 mL / min)

[0261] The plasma and urinary pharmacokinetics of migalastat have been investigated in healthy volunteers and Fabry patients with normal to mild renal impairment. In single-dose studies, migalastat had a moderate absorption rate, reaching peak concentrations approximately 3 hours (range, 1 to 6 hours) after oral administration across the entire dose range tested. Mean C max and AUC 0-t The values ​​increased dose-proportionally after oral doses of 75 mg to 1250 mg migalastat. The mean elimination half-life (t 1 / 2The mean urinary recovery time (TQT) ranged from 3.04 to 4.79 hours. The mean percentage of dose recovered in urine from the doses evaluated in the single ascending dose (SAD) study was 32.2%, 43.0%, 49.3%, and 48.5% for the 25 mg, 75 mg, 225 mg, and 675 mg dose groups, respectively. Only minimal accumulation of plasma migalastat was observed in the multiple ascending dose study. In the total quality of life (TQT) study, migalastat had a negative effect on cardiac repolarization at single doses of 150 mg and 1250 mg (Johnson et al., Clin Pharmacol Drug Dev. 2013 Apr;2(2):120-32).

[0262] In this single-dose renal impairment study conducted in non-Fabry subjects, plasma concentrations of a single 150 mg dose of migalastat HCl increased with increasing degrees of renal impairment compared with subjects with normal renal function. After a single oral dose of 150 mg of migalastat HCl, the mean plasma migalastat AUC 0-∞ was increased by 1.2-fold, 1.8-fold, and 4.5-fold in subjects with mild, moderate, or severe renal impairment, respectively, compared with healthy control subjects. 0-∞ The increase in values ​​was statistically significant in subjects with moderate or severe renal impairment, but not in subjects with mild renal impairment, compared with subjects with normal renal function after a single dose. max was slightly delayed in the severe group; C max Plasma migalastat C did not increase across groups after a single oral dose of 150 mg migalastat HCl in subjects with various degrees of renal impairment compared with healthy control subjects. 48 Levels were moderate (mainly Cr) compared to healthy control subjects. CL <50 mL / min) and in subjects with severe renal impairment. 1 / 2increased with increasing degree of renal impairment (arithmetic mean [min, max]: 6.4 [3.66, 9.47], 7.7 [3.81, 13.8], 22.2 [6.74, 48.3], and 32.3 [24.6, 48.0] hours for subjects with normal renal function and subjects with mild, moderate, or severe renal impairment, respectively). The mean CL / F decreased with increasing degree of renal failure, ranging from 12.1 to 2.7 L / hr for subjects with mild to severe renal impairment (Johnson, et al., American College of Clinical Pharmacology 4.4(2015):256-261).

[0263] Migalastat clearance decreased with increasing renal impairment, with migalastat HCl plasma t 1 / 2 , AUC 0-∞ , and C 48 The incidence of adverse events was similar across all renal function groups.

[0264] After a single oral dose of 150 mg migalastat HCl, plasma exposure (AUC 0-t (expressed as CL) increased with increasing degree of renal dysfunction. CR As the value decreases, the AUC of migalastat 0-t Figure 1B shows the mean (SE) plasma migalastat concentration-time profiles for each renal function group. BLQ values ​​were entered as 0 and included in the calculation of the mean values.

[0265] As shown in Figure 1C, the plasma migalastat AUC 0-t The results showed that, especially in subjects with severe renal impairment, the plasma clearance of migalastat decreased as renal impairment worsened, resulting in a decrease in t 1 / 2 becomes longer, and C 48 values ​​and overall plasma exposure (AUC 0-∞ ) was demonstrated. Migalastat is primarily excreted unchanged in the urine. Therefore, increased plasma migalastat exposure is consistent with worsening renal dysfunction.

[0266] Conclusion: Plasma migalastat clearance decreased with increasing degree of renal dysfunction.

[0267] A summary of the PK results is shown in Table 3 below.

[0268] TIFF2025143262000013.tif94170

[0269] Example 2: Multiple Dose Simulation for Renally Impaired Subjects In the renal impairment study of Example 1, the area under the curve (AUC) and trough concentration of migalastat at 48 hours post-dose following a QOD dose were significantly higher in subjects with eGFR values ​​≦35 mL / min compared to subjects with normal renal function (C 48 ) was observed.

[0270] A population PK model was developed to evaluate IC in Fabry patients with varying degrees of renal impairment. 50 This example provides a computer simulation of administration to subjects with renal impairment in Example 1. A key assumption was that the exposure characterized for non-Fabry subjects with renal impairment was the same as for Fabry patients with renal impairment. The software program was WinNonlin, version 5.2 or higher. The model conditions are described below. The modeling exercise included BSA-adjusted eGFR コッククロフト·ゴールト ≦35mL / min / 1.73m 2 Eleven subjects were included; three had moderate renal impairment but not >30 mL / min / 1.73 m 2 and ≤35 mL / min / 1.73 m 2 and 8 patients had a blood pressure of ≥ 14 mL / min / 1.73 m 2 and <30 mL / min / 1.73 m 2 Steady state was assumed by the seventh dose.

[0271] Vd and elimination rate constants were estimated from single-dose data using a two-compartment model, and these estimates were input into each molecular dose simulation regimen.

[0272] Figure 2 shows the mean simulated plots for the dosing regimen of 150 mg migalastat HCl QOD. Table 4 below shows the exposure and accumulation ratios.

[0273] Figure 3 shows the AUC vs. C from Example 1. 48 This stick plot shows the AUC and C across all levels of renal function. 48 A visual correlation of the concentrations is provided, demonstrating that these two values ​​correlate well visually.

[0274] TIFF2025143262000014.tif120170

[0275] Example 3: Pharmacokinetics of migalastat in Fabry patients with renal impairment The above computer modeling provides a scenario of plasma migalastat exposure but does not consider renal impairment in Fabry patients. That is, the data do not include a pharmacodynamic component (plasma lyso-GB3). Therefore, two Fabry patients with renal impairment were evaluated. One patient (P1) had moderate renal impairment, and the other patient (P2) had severe renal impairment. Table 5 below shows the plasma migalastat concentrations in P1 compared with the ERT-naive Fabry patient study and the moderately impaired subject from the renal impairment study in Example 1. There were two sets of migalastat concentration measurements taken six months apart, and the patient had previously been treated with migalastat. Table 6 shows similar information for P2, but compared with the severely impaired patient from the renal impairment study in Example 1. An ERT-naive study was conducted in Fabry patients with applicable mutations, in which population PK was performed from sparse blood sampling. Comparison with the results of the ERT-naive study allows for comparison of the PK in the Fabry population, which includes mostly normal, but some mildly and some moderately impaired Fabry patients. Patients with severe renal impairment were not present in the ERT-naive study because they were excluded from the study.

[0276] TIFF2025143262000015.tif73170

[0277] TIFF2025143262000016.tif55170

[0278] As can be seen in Table 5, C 48 Concentrations increased by 49% but remained similar to those in non-Fabry subjects with moderate renal impairment in Example 1. max Although the value of C has increased by 33%, it remains the same as in Example 1. 24 The eGFR is the same as in Example 1 for moderate renal impairment. MDRD also remained within the range of moderate impairment (32 mL / min).

[0279] The percentages in parentheses are the coefficients of variation, which are relatively high and correspond to the variability of the time 0 h or time 48 h concentrations. This result is likely due to half of the subjects from Example 1 with moderate renal impairment having low concentrations and half having high concentrations.

[0280] For P1, the concentration at 48 hours is higher than the concentration at time 0 (columns 3 and 4), but for the moderately impaired person from Example 1, the concentration at 48 hours is the same as at time 0. This is because for P1, separate blood samples were taken at time 0 and time 48. However, Example 1 used the repeat dose modeling simulation output from the single dose data, so the values ​​are identical.

[0281] A similar trend can be seen in Table 6. Thus, Tables 5 and 6 confirm similar migalastat pharmacokinetics in Fabry and non-Fabry patients with similar renal impairment.

[0282] FIG. 4 shows the plasma migalastat trough concentrations (C) of Fabry patients for the renal dysfunction study of Example 1. 48 ) is shown. Figure 5 shows the mean (SD) renal impairment study exposure versus estimated AUC in Fabry patients. As can be seen in this figure, P1 and P2 followed the general trend of renal impairment study results in non-Fabry patients.

[0283] Table 7 below shows Lyso-GB3 / eGFR for P1.

[0284] TIFF2025143262000017.tif73170

[0285] 32mL / min / 1.73m 2 Despite continued deterioration in renal function down to an eGFR of , plasma lyso-GB3 showed no clinically relevant changes from the previous visit, and plasma migalastat concentrations remained similar to those observed in non-Fabry patients with moderate renal impairment.

[0286] This study demonstrates that trends in renal dysfunction and pharmacokinetics in Fabry patients correlate with trends in non-Fabry patients.

[0287] Example 4: Additional Simulations for Renally Impaired Subjects This example provides an additional computer simulation of migalastat administration to subjects with renal impairment from Example 1.

[0288] Figures 6A-6D show simulated median and measured migalastat concentrations over time in normal, severe, mild, and moderately impaired renal subjects, respectively. The data are presented in Table 8 below:

[0289] TIFF2025143262000018.tif98170

[0290] 7A to 7D show simulated C for normal, mild, moderate, and severe renal impairment subjects, respectively. max ,AUC,C min and C 48 Shows.

[0291] Figures 8A-8D show steady-state predictions of QOD. The dashed lines are the average values ​​from the QT study. Figures 9A-9D show the C, C, and C, respectively, for the same simulations. max ,AUC,C min and C 48 Shows.

[0292] Example 5: Clinical results of migalastat therapy in Fabry patients with renal dysfunction and / or hyperproteinuria As noted above, several studies have been conducted using 150 mg migalastat hydrochloride every other day (QOD) in Fabry patients. One study was a 24-month study with a 6-month double-blind, placebo-controlled period in 67 ERT-naive patients. The other study was an 18-month, active-controlled study in 57 ERT-experienced patients with a 12-month open-label extension (OLE). Both the ERT-naive and ERT-experienced studies included patients with an eGFR of ≥ 30 mL / min / 1.73 m 2 Fabry patients were included. The study designs of these studies are shown in Figures 10A-10B.

[0293] In the ERT-experienced study, the primary efficacy parameter was GFR measurement using iohexol clearance (mGFR イオヘキソール ) and eGFR (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. CKD-EPI ) annual change from baseline to 18 months (mL / min / 1.73m 2 / year. The eGFR (eGFR MDRD ) were also calculated.

[0294] In the ERT-naive study, the primary efficacy parameter was the number of GL-3 inclusions per renal interstitial capillary. イオヘキソール , eGFR CKD-EPI and eGFR MDRD Renal function was also assessed by

[0295] A post-hoc analysis of data from ERT-naive trials showed that patients with moderate renal impairment (30 to <60 mL / min / 1.73 m 2 ), mild renal dysfunction (60 to <90 mL / min / 1.73 m 2 ), and normal renal function (≥90 mL / min / 1.73 m 2eGFR in subgroups based on baseline eGFR for eligible patients with CKD-EPI The annual rate of change in eGFR from baseline to 18 / 24 months was examined. CKD-EPI The annual change rate is shown in Figure 11. As can be seen from Figure 11, patients with moderate renal dysfunction had a high eGFR CKD-EPI The mean annual rate of change ± SEM was -0.7 ± 3.97 mL / min / 1.73 m 2 / year, and patients with mild renal dysfunction had an eGFR CKD-EPI The mean annual rate of change was -0.8±1.01 mL / min / 1.73 m 2 / year, and patients with normal renal function had an eGFR CKD-EPI The mean annual rate of change was 0.2±0.90 mL / min / 1.73 m 2 The data indicate that stabilization of renal function with migalastat treatment was observed regardless of baseline eGFR.

[0296] A post-hoc analysis of data from the ERT-experienced trial found that patients with mild / moderate renal impairment (30 to <90 mL / min / 1.73 m 2 ) and normal renal function (≥ 90 mL / min / 1.73 m 2 eGFR in subgroups based on baseline eGFR for patients with CKD-EPI and mGFR イオヘキソール The annual rate of change in eGFR was investigated. The annual rate of change from baseline to 18 months was calculated for patients receiving migalastat therapy (patients with applicable mutations) and patients receiving ERT, respectively. CKD-EPI and mGFR イオヘキソール As can be seen from FIG. 12A, patients with normal renal function had an eGFR CKD-EPI The mean annual change rate was -0.4 mL / min / 1.73 m with migalastat therapy. 2 / year and ERT -1.03mL / min / 1.73m 2 Patients with mild or moderate renal impairment had a higher eGFR CKD-EPI The mean annual change rate was -3.33 mL / min / 1.73 m with migalastat therapy. 2 / year and ERT -9.05mL / min / 1.73m2 As can be seen from Figure 12B, patients with normal renal function had an mGFR イオヘキソール The mean annual change rate was -4.35 mL / min / 1.73 m with migalastat therapy. 2 / year and ERT -3.24mL / min / 1.73m 2 Patients with mild or moderate renal impairment had a mGFR イオヘキソール The mean annual change rate was -3.51 mL / min / 1.73 m with migalastat therapy. 2 / year and ERT -7.96mL / min / 1.73m 2 The data show that migalastat therapy and ERT had similar favorable effects on renal function using both GFR methods.

[0297] Another post-hoc analysis of data from the ERT-experienced trial found that patients with moderate renal impairment (30 to <60 mL / min / 1.73 m 2 ), mild renal dysfunction (60 to <90 mL / min / 1.73 m 2 ), and normal renal function (≥90 mL / min / 1.73 m 2 eGFR in subgroups based on baseline eGFR for patients with CKD-EPI The annual rate of change was investigated. The annual rate of change from baseline to 18 months for patients receiving migalastat therapy (patients with applicable mutations) and patients receiving ERT is shown in Figure 13. As can be seen from Figure 13, patients with normal renal function had a high eGFR CKD-EPI The mean annual rate of change ± SE was -2.0 ± 0.57 mL / min / 1.73 m with migalastat therapy. 2 / year and ERT -2.1±1.60mL / min / 1.73m 2 / year. Patients with mild renal dysfunction had an eGFR CKD-EPI The mean annual change ± SE was -0.2 ± 1.25 mL / min / 1.73 m with migalastat therapy. 2 / year and ERT -7.3±6.01mL / min / 1.73m 2 / year. Patients with moderate renal dysfunction had an eGFR CKD-EPIThe mean annual rate of change ± SE was -4.5 ± 2.68 mL / min / 1.73 m with migalastat therapy. 2 / year and ERT 1.3mL / min / 1.73m 2 / year. The data indicate that migalastat stabilized renal function regardless of whether the patients had normal renal function or mild renal impairment. Although the number of patients with moderate renal impairment included in this analysis was two (compared to three in the ERT-naive study), the data support the efficacy of migalastat when administered to patients with any form of renal impairment.

[0298] Further analysis of data from these trials will reveal eGFR based on baseline renal function. CKD-EPI Annualized percent change, LVMi, WBC α-Gal A activity, and plasma lyso-Gb3 levels were examined. The results for each renal subgroup are shown in Table 9 below, where the ERT-naive study subgroup had eGFR MDRD Based on the mGFR and ERT-experienced study subgroups イオヘキソール Based on.

[0299] TIFF2025143262000019.tif134170

[0300] As can be seen in Table 9, in the ERT-naive study, migalastat reduced plasma lyso-Gb3 and LVMi and increased WBC α-Gal A activity at 24 months in both renal subgroups. Furthermore, in the ERT-naive study, regardless of renal function, migalastat reduced renal interstitial capillary GL-3 inclusions from baseline to 6 months, but did not significantly reduce renal interstitial capillary GL-3 inclusions (eGFR < 60 mL / min / 1.73 m). 2 , -0.39, n=3;eGFR≧60mL / min / 1.73m 2, -0.30, n=22), but not placebo (<60, 0.04, n=2; ≥60, 0.07, n=18). Table 9 also shows that in the ERT-experienced study, LVMi decreased, WBC α-Gal A activity increased, and lyso-Gb3 remained low and stable during 18 months of treatment with migalastat in both renal subgroups. Table 9 also shows that baseline eGFR ≥60 mL / min / 1.73 m in both the ERT-naive and ERT-experienced studies 2 The data also show that renal function stabilized in 10 patients. This data further supports the efficacy of migalastat when administered to patients with some form of renal impairment.

[0301] In addition to the studies described above, other patients also received migalastat therapy in other studies, such as dose-finding and / or long-term extension studies. Patients who completed some studies were eligible to continue on open-label migalastat HCl 150 mg every other day in a separate extension study.

[0302] Twelve patients who completed multiple trials were further analyzed. Linear regression was used to measure the change in eGFR from baseline. CKD-EPI The annual percentage change in serotonin was calculated. At the time of this analysis, the mean time receiving migalastat for these 12 patients was 8.2 (standard deviation [SD], 0.83) years, the median time on treatment was 8.4 (range, 6.3-9.3) years, and 11 patients had received migalastat HCl 150 mg QOD for ≥ 17 months. The baseline demographic characteristics of these 12 patients are shown below in Table 10:

[0303] TIFF2025143262000020.tif141170

[0304] eGFR in these patients CKD-EPI The annual changes are shown in Table 11 below:

[0305] TIFF2025143262000021.tif164170

[0306] As can be seen in Table 11, renal function remained stable (eGFR) among these 12 patients over the entire migalastat treatment period (mean exposure, 8.2 years). CKD-EPI mean annual change of -0.67 mL / min / 1.72 m 2 Renal function also remained stable (eGFR [95% CI -1.32, -0.02]) in an analysis of 11 patients who received migalastat HCl 150 mg QOD for ≥17 months (mean exposure, 4-5 years). CKD-EPI The average annual change in 2 [95% CI -1.7, 2.2]). The renal outcomes of these 11 patients based on gender and baseline proteinuria levels are shown in Table 12 below:

[0307] TIFF2025143262000022.tif78170

[0308] These results demonstrate stabilization of renal function in male and female patients with Fabry disease and applicable mutations treated with migalastat for up to 9 years, an effect observed across a wide range of baseline proteinuria.

[0309] A separate analysis was performed for patients enrolled in multiple trials of migalastat use. Patients' eGFR was assessed based on baseline proteinuria (<100, 100-1000, >1000 mg / 24 hr). CKD-EPI and eGFR MDRD The annual percentage change in proteinuria was calculated. A total of 52 ERT-naive patients with applicable mutations who received migalastat HCl 150 mg QOD for ≥ 17 months were analyzed. Table 13 below shows the baseline proteinuria and duration of migalastat treatment for these patients.

[0310] TIFF2025143262000023.tif58170

[0311] As can be seen in Table 13, most patients (67%) had proteinuria levels of 100 to 1000 mg / 24 h at baseline; 23% of patients had baseline proteinuria levels <100 mg / 24 h, and 10% had levels >1000 mg / 24 h. Median treatment duration ranged from 3.5 to 4.8 years (maximum, 5.3 years) across all baseline proteinuria subgroups.

[0312] eGFR with migalastat treatment according to baseline proteinuria in these patients CKD-EPI The average annual change is shown in Table 14 below.

[0313] TIFF2025143262000024.tif73170

[0314] As can be seen from Table 14, most patients with baseline proteinuria ≤ 1000 mg / 24 h had an eGFR CKD-EPI In patients with baseline proteinuria levels >1000 mg / 24 h, eGFR remained stable. CKD-EPI A worsening of the condition was observed.

[0315] eGFR MDRD The results were compared with eGFR reported in the literature for untreated patients with Fabry disease. MDRD The changes were compared with those in the natural history cohort (Schiffmann R et al. Nephrol Diarrhea Transplant. 2009;24:2102-11), as shown in Table 15 below:

[0316] TIFF2025143262000025.tif125170

[0317] As shown in Table 15, mean annual changes in eGFR were generally smaller in migalastat-treated patients compared with those observed in the natural history cohort across all proteinuria categories. Mean eGFR worsened in all treatment-naive subgroups, but increases with migalastat were observed in patients with baseline proteinuria <100 mg / 24 h (men) and 100-1000 mg / 24 h (men and women). Regardless of treatment, eGFR declined in patients with baseline proteinuria >1000 mg / 24 h; however, declines were smaller in migalastat-treated patients compared with the natural history cohort. Thus, long-term migalastat treatment was associated with generally stable renal function in patients with Fabry disease and applicable mutations, regardless of baseline proteinuria levels.

[0318] The patents and scientific literature referred to herein establish knowledge available to those skilled in the art. All U.S. patents and published or unpublished U.S. patent applications cited herein are incorporated by reference. All published foreign patents and patent applications cited herein are hereby incorporated by reference. All other published references, documents, articles and scientific literature cited herein are hereby incorporated by reference.

[0319] While the present invention has been particularly shown and described with reference to preferred embodiments thereof, workers skilled in the art will understand that various changes in form and details may be made therein without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. 1. A method for stabilizing renal function in a patient diagnosed with Fabry disease and having impaired renal function, comprising administering to the patient an effective amount of migalastat or a salt thereof once every other day, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE), and wherein the administration of migalastat or a salt thereof is effective to stabilize the renal function of the patient.

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

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

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

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

6. The method of any one of claims 1 to 5, wherein the patient is an enzyme replacement therapy (ERT)-experienced patient.

7. The method of any one of claims 1 to 5, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

8. The method according to any one of claims 1 to 7, wherein the patient has a proteinuria level of less than 100 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

9. The method according to any one of claims 1 to 7, wherein the patient has a proteinuria level of 100 to 1,000 mg / 24 hr before starting administration of the migalastat or a salt thereof.

10. The method according to any one of claims 1 to 7, wherein the patient has a proteinuria level of greater than 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

11. The method of any one of claims 1 to 10, wherein the migalastat or a salt thereof is in a solid dosage form.

12. The method of any one of claims 1 to 11, wherein the migalastat or a salt thereof is administered orally.

13. The method of any one of claims 1 to 12, wherein the migalastat or a salt thereof is administered for at least 28 days.

14. The method of any one of claims 1 to 13, wherein the migalastat or a salt thereof is administered for at least 6 months.

15. The method of any one of claims 1 to 14, wherein the migalastat or a salt thereof is administered for at least 12 months.

16. The administration of the effective amount of migalastat or a salt thereof to a group of patients with mild or moderate renal impairment results in a renal flow rate of -1.0 mL / min / 1.73 m ２ Larger eGFR ＣＫＤ－ＥＰＩ The method of any one of claims 1 to 15, which results in an average annual rate of change of

17. The administration of the effective amount of migalastat or a salt thereof to a group of patients with mild renal impairment is ２ Larger eGFR ＣＫＤ－ＥＰＩ The method of any one of claims 1 to 16, resulting in an average annual rate of change of

18. The administration of the effective amount of migalastat or a salt thereof to a group of patients with moderate renal impairment results in a renal flow rate of -1.0 mL / min / 1.73 m ２ Larger eGFR ＣＫＤ－ＥＰＩ 18. The method of any one of claims 1 to 17, which results in an average annual rate of change of

19. 19. The method of any one of claims 1-18, wherein the effective amount is about 123 mg FBE.

20. 20. The method of any one of claims 1 to 19, wherein the effective amount is about 123 mg of migalastat free base.

21. 20. The method of any one of claims 1 to 19, wherein the effective amount is about 150 mg of migalastat hydrochloride.

22. The method of any one of claims 1 to 21, wherein the patient has a HEK assay-amenable mutation in α-galactosidase A.

23. 1. A method for treating Fabry disease in a patient diagnosed with Fabry disease and having impaired renal function, comprising administering to the patient an effective amount of migalastat or a salt thereof once every other day, wherein the effective amount is from about 100 mg to about 150 mg free base equivalent (FBE).

24. 24. The method of claim 23, wherein the patient has mild or moderate renal impairment.

25. 24. The method of claim 23, wherein the patient has mild renal impairment.

26. 24. The method of claim 23, wherein the patient has moderate renal impairment.

27. 24. The method of claim 23, wherein the patient has severe renal impairment.

28. The method of any one of claims 23 to 27, wherein the patient is an enzyme replacement therapy (ERT) experienced patient.

29. The method of any one of claims 23 to 27, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

30. The method according to any one of claims 23 to 29, wherein the patient has a proteinuria level of less than 100 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

31. The method according to any one of claims 23 to 29, wherein the patient has a proteinuria level of 100 to 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

32. The method according to any one of claims 23 to 29, wherein the patient has a proteinuria level of greater than 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

33. 33. The method of any one of claims 23 to 32, wherein the migalastat or salt thereof is in a solid dosage form.

34. The method of any one of claims 23 to 33, wherein the migalastat or a salt thereof is administered orally.

35. The method of any one of claims 23 to 34, wherein the migalastat or a salt thereof is administered for at least 28 days.

36. 36. The method of any one of claims 23 to 35, wherein the migalastat or a salt thereof is administered for at least 6 months.

37. 37. The method of any one of claims 23 to 36, wherein the migalastat or a salt thereof is administered for at least 12 months.

38. 38. The method of any one of claims 23 to 37, wherein administration of migalastat or a salt thereof is effective to increase α-galactosidase A (α-Gal A) activity in the patient.

39. 39. The method of claim 38, wherein the α-Gal A activity is white blood cell (WBC) α-Gal A activity.

40. 40. The method of any one of claims 23 to 39, wherein administration of the migalastat or a salt thereof is effective to reduce the left ventricular mass index (LVMi) of the patient.

41. The administration of migalastat or a salt thereof increases plasma globotriaosylsphingosine (lyso-Gb ３ 41. The method of any one of claims 23 to 40, wherein the method is effective to stabilize

42. 42. The method of any one of claims 23 to 41, wherein administration of the migalastat or a salt thereof is effective to stabilize renal function in the patient.

43. 43. The method of any one of claims 23-42, wherein the effective amount is about 123 mg FBE.

44. 44. The method of any one of claims 23-43, wherein the effective amount is about 123 mg of migalastat free base.

45. 44. The method of any one of claims 23 to 43, wherein the effective amount is about 150 mg of migalastat hydrochloride.

46. The method of any one of claims 23 to 45, wherein the patient has a HEK assay-amenable mutation in α-galactosidase A.

47. Plasma globotriaosylsphingosine (lyso-Gb) levels in patients diagnosed with Fabry disease and with renal dysfunction ３ ), comprising administering to the patient an effective amount of migalastat or a salt thereof once every other day, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE), and the administration of migalastat or a salt thereof increases plasma lyso-Gb in the patient. ３ The method is effective in stabilizing

48. 48. The method of claim 47, wherein the patient has mild or moderate renal impairment.

49. 48. The method of claim 47, wherein the patient has mild renal impairment.

50. 48. The method of claim 47, wherein the patient has moderate renal impairment.

51. 48. The method of claim 47, wherein the patient has severe renal impairment.

52. 51. The method of any one of claims 47 to 50, wherein the patient is an enzyme replacement therapy (ERT) experienced patient.

53. 52. The method of any one of claims 47 to 51, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

54. The method of any one of claims 47 to 53, wherein the patient has a proteinuria level of less than 100 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

55. The method according to any one of claims 47 to 53, wherein the patient has a proteinuria level of 100 to 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

56. The method of any one of claims 47 to 53, wherein the patient has a proteinuria level greater than 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

57. 57. The method of any one of claims 47 to 56, wherein the migalastat or salt thereof is in a solid dosage form.

58. 58. The method of any one of claims 47 to 57, wherein the migalastat or a salt thereof is administered orally.

59. 59. The method of any one of claims 47 to 58, wherein the migalastat or a salt thereof is administered for at least 28 days.

60. 60. The method of any one of claims 47 to 59, wherein the migalastat or a salt thereof is administered for at least 6 months.

61. 61. The method of any one of claims 47 to 60, wherein the migalastat or a salt thereof is administered for at least 12 months.

62. Administration of the effective amount of migalastat or a salt thereof to a group of ERT-naive patients with moderate renal impairment results in a plasma lyso-Gb of at least about 5 nmol / L after 24 months of administration of the migalastat or a salt thereof. ３ 62. The method of any one of claims 47 to 61, resulting in an average reduction of

63. 63. The method of any one of claims 47-62, wherein the effective amount is about 123 mg FBE.

64. 64. The method of any one of claims 47-63, wherein the effective amount is about 123 mg of migalastat free base.

65. 65. The method of any one of claims 47 to 64, wherein the effective amount is about 150 mg of migalastat hydrochloride.

66. The method of any one of claims 47 to 65, wherein the patient has a HEK assay-amenable mutation in α-galactosidase A.

67. A method for reducing left ventricular mass index (LVMi) in a patient diagnosed with Fabry disease and having impaired renal function, comprising administering to the patient an effective amount of migalastat or a salt thereof once every other day, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE), and wherein the administration of migalastat or a salt thereof is effective to reduce the patient's LVMi.

68. 68. The method of claim 67, wherein the patient has mild or moderate renal impairment.

69. 68. The method of claim 67, wherein the patient has mild renal impairment.

70. 68. The method of claim 67, wherein the patient has moderate renal impairment.

71. 68. The method of claim 67, wherein the patient has severe renal impairment.

72. 72. The method of any one of claims 67 to 71, wherein the patient is an enzyme replacement therapy (ERT) experienced patient.

73. 72. The method of any one of claims 67 to 71, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

74. 74. The method of any one of claims 67 to 73, wherein the patient has a proteinuria level of less than 100 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

75. The method according to any one of claims 67 to 73, wherein the patient has a proteinuria level of 100 to 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

76. The method of any one of claims 67 to 73, wherein the patient has a proteinuria level greater than 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

77. 77. The method of any one of claims 67 to 76, wherein the migalastat or salt thereof is in a solid dosage form.

78. 78. The method of any one of claims 67 to 77, wherein the migalastat or a salt thereof is administered orally.

79. 79. The method of any one of claims 67 to 78, wherein the migalastat or a salt thereof is administered for at least 28 days.

80. 80. The method of any one of claims 67 to 79, wherein the migalastat or a salt thereof is administered for at least 6 months.

81. 81. The method of any one of claims 67 to 80, wherein the migalastat or a salt thereof is administered for at least 12 months.

82. administration of the effective amount of migalastat or a salt thereof to a group of ERT-naive patients with moderate renal impairment results in a blood glucose level of at least about 2 g / m after 24 months of administration of the migalastat or a salt thereof; ２ 82. The method of any one of claims 67 to 81, resulting in a mean decrease in LVMi of

83. administration of the effective amount of migalastat or a salt thereof to a group of ERT-experienced patients with moderate renal impairment results in a renal function of at least about 2 g / m after 18 months of administration of the migalastat or a salt thereof; ２ 83. The method of any one of claims 67 to 82, resulting in a mean decrease in LVMi of

84. 84. The method of any one of claims 67-83, wherein the effective amount is about 123 mg FBE.

85. 85. The method of any one of claims 67-84, wherein the effective amount is about 123 mg of migalastat free base.

86. 85. The method of any one of claims 67 to 84, wherein the effective amount is about 150 mg of migalastat hydrochloride.

87. The method of any one of claims 67 to 86, wherein the patient has a HEK assay-amenable mutation in α-galactosidase A.

88. 1. A method for increasing white blood cell (WBC) α-galactosidase A (α-Gal A) activity in a patient diagnosed with Fabry disease and having impaired renal function, comprising administering to the patient an effective amount of migalastat or a salt thereof once every other day, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE), and wherein the administration of migalastat or a salt thereof is effective to increase WBC α-Gal A activity in the patient.

89. 89. The method of claim 88, wherein the patient has mild or moderate renal impairment.

90. 89. The method of claim 88, wherein the patient has mild renal impairment.

91. 89. The method of claim 88, wherein the patient has moderate renal impairment.

92. 89. The method of claim 88, wherein the patient has severe renal impairment.

93. 93. The method of any one of claims 88 to 92, wherein the patient is an enzyme replacement therapy (ERT) experienced patient.

94. 93. The method of any one of claims 88 to 92, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

95. 95. The method of any one of claims 88 to 94, wherein the patient has a proteinuria level of less than 100 mg / 24 hr before initiating administration of the migalastat or salt thereof.

96. The method of any one of claims 88 to 94, wherein the patient has a proteinuria level of 100 to 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

97. The method of any one of claims 88 to 94, wherein the patient has a proteinuria level greater than 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

98. 98. The method of any one of claims 88 to 97, wherein the migalastat or salt thereof is in a solid dosage form.

99. 99. The method of any one of claims 88 to 98, wherein the migalastat or a salt thereof is administered orally.

100. 100. The method of any one of claims 88 to 99, wherein the migalastat or a salt thereof is administered for at least 28 days.

101. 101. The method of any one of claims 88 to 100, wherein the migalastat or a salt thereof is administered for at least 6 months.

102. 102. The method of any one of claims 88 to 101, wherein the migalastat or a salt thereof is administered for at least 12 months.

103. The method of any one of claims 88 to 102, wherein administration of the effective amount of migalastat or a salt thereof to a group of ERT-naive patients with moderate renal impairment results in a mean increase in WBC α-Gal A activity of at least about 1.4MU / hr / mg after 24 months of administration of the migalastat or a salt thereof.

104. The method of any one of claims 88 to 103, wherein administration of the effective amount of migalastat or a salt thereof to a population of ERT-experienced patients with moderate renal impairment results in a mean increase in WBC α-Gal A activity of at least about 1.4MU / hr / mg after 18 months of administration of the migalastat or a salt thereof.

105. 105. The method of any one of claims 88-104, wherein the effective amount is about 123 mg FBE.

106. 106. The method of any one of claims 88-105, wherein the effective amount is about 123 mg of migalastat free base.

107. 106. The method of any one of claims 88-105, wherein the effective amount is about 150 mg of migalastat hydrochloride.

108. The method of any one of claims 88 to 107, wherein the patient has a HEK assay-amenable mutation in α-galactosidase A.

109. 1. A method for stabilizing renal function in a patient diagnosed with Fabry disease and having hyperproteinuria, comprising administering to the patient an effective amount of migalastat or a salt thereof once every other day, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE), and wherein the administration of migalastat or a salt thereof is effective to stabilize the renal function of the patient.

110. 110. The method of claim 109, wherein the patient has impaired renal function.

111. 111. The method of claim 110, wherein the patient has mild renal impairment.

112. 111. The method of claim 110, wherein the patient has moderate renal impairment.

113. 111. The method of claim 110, wherein the patient has severe renal impairment.

114. 114. The method of any one of claims 109 to 113, wherein the patient is an enzyme replacement therapy (ERT) experienced patient.

115. The method of any one of claims 109 to 113, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

116. The method of any one of claims 109 to 115, wherein the patient has a proteinuria level of 100 to 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

117. The method of any one of claims 109 to 115, wherein the patient has a proteinuria level greater than 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

118. 118. The method of any one of claims 109 to 117, wherein the migalastat or salt thereof is in a solid dosage form.

119. 119. The method of any one of claims 109 to 118, wherein the migalastat or a salt thereof is administered orally.

120. 120. The method of any one of claims 109 to 119, wherein the migalastat or a salt thereof is administered for at least 28 days.

121. 121. The method of any one of claims 109 to 120, wherein the migalastat or a salt thereof is administered for at least 6 months.

122. 122. The method of any one of claims 109 to 121, wherein the migalastat or a salt thereof is administered for at least 12 months.

123. The administration of the effective amount of migalastat or a salt thereof to a group of patients having a proteinuria level of 100 to 1,000 mg / 24 hr before the start of administration of migalastat or a salt thereof results in a proteinuria rate of -2.0 mL / min / 1.73 m ２ Larger eGFR ＣＫＤ－ＥＰＩ 123. The method of any one of claims 109 to 122, resulting in an average annual rate of change of

124. The administration of the effective amount of migalastat or a salt thereof to a group of patients having a proteinuria level of more than 1,000 mg / 24 hr before the start of administration of migalastat or a salt thereof results in a proteinuria rate of -5.0 mL / min / 1.73 m ２ Larger eGFR ＣＫＤ－ＥＰＩ 124. The method of any one of claims 109 to 123, resulting in an average annual rate of change of

125. 125. The method of any one of claims 109-124, wherein the effective amount is about 123 mg FBE.

126. 126. The method of any one of claims 109-125, wherein the effective amount is about 123 mg of migalastat free base.

127. 126. The method of any one of claims 109-125, wherein the effective amount is about 150 mg of migalastat hydrochloride.

128. The method of any one of claims 109 to 127, wherein the patient has a HEK assay-amenable mutation in α-galactosidase A.

129. 1. A method for treating Fabry disease in a patient diagnosed with Fabry disease and having hyperproteinuria, comprising administering to said patient an effective amount of migalastat or a salt thereof once every other day, said effective amount being from about 100 mg to about 150 mg free base equivalent (FBE).

130. 130. The method of claim 129, wherein the patient has impaired renal function.

131. 131. The method of claim 130, wherein the patient has mild renal impairment.

132. 131. The method of claim 130, wherein the patient has moderate renal impairment.

133. 131. The method of claim 130, wherein the patient has severe renal impairment.

134. 134. The method of any one of claims 129 to 133, wherein the patient is an enzyme replacement therapy (ERT) experienced patient.

135. 134. The method of any one of claims 129 to 133, wherein the patient is an enzyme replacement therapy (ERT) naive patient.

136. The method of any one of claims 129 to 134, wherein the patient has a proteinuria level of 100 to 1,000 mg / 24 hr before initiating administration of the migalastat or a salt thereof.

137. The method of any one of claims 129 to 134, wherein the patient has a proteinuria level greater than 1,000 mg / 24 hr before initiating administration of the migalastat or salt thereof.

138. 138. The method of any one of claims 129 to 137, wherein the migalastat or salt thereof is in a solid dosage form.

139. 139. The method of any one of claims 129 to 138, wherein the migalastat or a salt thereof is administered orally.

140. 140. The method of any one of claims 129 to 139, wherein the migalastat or a salt thereof is administered for at least 28 days.

141. 141. The method of any one of claims 129 to 140, wherein the migalastat or a salt thereof is administered for at least 6 months.

142. 142. The method of any one of claims 129 to 141, wherein the migalastat or a salt thereof is administered for at least 12 months.

143. The administration of the effective amount of migalastat or a salt thereof to a group of patients having a proteinuria level of 100 to 1,000 mg / 24 hr before the start of administration of migalastat or a salt thereof results in a proteinuria rate of -2.0 mL / min / 1.73 m ２ Larger eGFR ＣＫＤ－ＥＰＩ 143. The method of any one of claims 129 to 142, resulting in an average annual rate of change of

144. The administration of the effective amount of migalastat or a salt thereof to a group of patients having a proteinuria level of more than 1,000 mg / 24 hr before the start of administration of migalastat or a salt thereof results in a proteinuria rate of -5.0 mL / min / 1.73 m ２ Larger eGFR ＣＫＤ－ＥＰＩ 144. The method of any one of claims 129 to 143, which results in an average annual rate of change of

145. 145. The method of any one of claims 129-144, wherein the effective amount is about 123 mg FBE.

146. 146. The method of any one of claims 129-145, wherein the effective amount is about 123 mg of migalastat free base.

147. 147. The method of any one of claims 129 to 146, wherein the effective amount is about 150 mg of migalastat hydrochloride.

148. The method of any one of claims 129 to 147, wherein the patient has a HEK assay-amenable mutation in α-galactosidase A.

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