Method of treating Fabry patients with renal injury

Abstract

Methods for treating Fabry Disease in a patient with renal injury and / or elevated proteinuria are provided. Certain methods include administering to the patient from about 100 to about 150 mg of free base equivalents of migaxostat, or a salt thereof, once every day. Certain methods also provide for stabilizing renal function, reducing left ventricular mass index, reducing plasma globulin triosyl sphingosine, and / or increasing alpha-galactosidase A activity in the patient.

Description

This application is a divisional application of the invention patent application with application number 201880043564.X filed on May 30, 2018, and invention name “Method for treating Fabry patients with renal damage”. Technical Field

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

[0002] Many human diseases are caused by mutations that cause changes in the amino acid sequence of proteins, which reduce protein stability and may prevent them from folding correctly. Proteins are usually folded in a specific area of ​​the cell called the endoplasmic reticulum or ER. Cells have quality control mechanisms that ensure that proteins are folded into their correct three-dimensional shapes before they can move from the ER to the appropriate destination in the cell (a process commonly referred to as protein transport). Misfolded proteins are usually eliminated by quality control mechanisms after initially being retained in the ER. In some cases, misfolded proteins can accumulate in the ER before being eliminated. The retention of misfolded proteins in the ER interrupts their correct transportation, and the resulting reduced biological activity may cause impaired cell function and ultimately lead to disease. In addition, the accumulation of misfolded proteins in the ER may cause various types of stress on cells, which may also contribute to cellular dysfunction and disease.

[0003] Such mutations may lead to lysosomal storage disorders (LSDs), which are characterized by lysosomal enzyme deficiency caused by mutations in genes encoding lysosomal enzymes. The diseases resulting from such mutations lead to pathological accumulation of substrates for those enzymes, including lipids, carbohydrates, and polysaccharides. Although there are many different mutant genotypes associated with each LSD, many mutations are missense mutations, which may lead to the production of more unstable enzymes. These more unstable enzymes are sometimes prematurely degraded by the degradation pathways associated with the ER. This leads to enzyme deficiency in the lysosome and pathological accumulation of substrates. Such mutant enzymes are sometimes referred to as "folding mutants" or "conformation mutants" in the relevant art.

[0004] Fabry disease is a LSD caused by mutations in the GLA gene, which encodes the enzyme alpha-galactosidase A (α-GalA). α-Gal A is required for glycosphingolipid metabolism. The mutation results in the accumulation of the substrate globotriaosylceramide (GL-3) in various tissues and organs. Males with Fabry disease are hemizygous because the disease gene is encoded on the X chromosome. Fabry disease is estimated to affect between 1 in 40,000 and 1 in 60,000 males and occurs less frequently in females.

[0005] There are several approaches to treat Fabry disease. One approved therapy for the treatment of Fabry disease is enzyme replacement therapy (ERT), which generally involves intravenous infusion of a purified form of the corresponding wild-type protein. Two α-Gal A products are currently available for the treatment of Fabry disease: α-galactosidase ( , Shire HumanGenetic Therapies) and β-galactosidase ( ; Sanofi Genzyme Corporation). However, ERT has several disadvantages. One of the major complications of ERT is the rapid degradation of the infused protein, which results in the need for large, expensive, high-dose infusions. ERT has several additional caveats, such as difficulty in large-scale production, purification, and storage of correctly folded proteins; obtaining glycosylated native proteins; generating anti-protein immune responses; and the inability of proteins to cross the blood-brain barrier to alleviate central nervous system pathologies (i.e., low bioavailability). In addition, replacement enzymes cannot penetrate the heart or kidneys in sufficient quantities to reduce substrate accumulation in renal podocytes or cardiomyocytes, which is prominent in Fabry disease.

[0006] Another approach to treating some enzyme deficiencies involves the use of small molecule inhibitors to reduce the production of the natural substrate of the defective enzyme protein, thereby ameliorating the condition. This "substrate reduction" approach has been specifically described for a class of about 40 LSDs, including the glycosphingolipid storage disorders. The small molecule inhibitors proposed for use as therapies specifically inhibit enzymes involved in glycolipid synthesis, thereby reducing the amount of cellular glycolipids that need to be broken down by the defective enzyme.

[0007] A third approach to treating Fabry disease is treatment with so-called pharmacological chaperones (PCs). Such PCs include small molecule inhibitors of α-Gal A, which can bind to α-Gal A to increase the stability of the mutant enzyme and the corresponding wild-type.

[0008] One problem with current treatments is that it is difficult to treat patients who exhibit renal impairment, which is very common in Fabry patients and progresses with the disease. On average, it takes about 10-20 years for patients to decline from normal renal function to severe renal impairment, and some countries report even faster declines. According to some estimates, about 10% of Fabry patients receiving ERT may have moderate renal impairment. Another 25% of men and 5% of women receiving ERT have an estimated glomerular filtration rate (eGFR) below 30, which corresponds to severe renal impairment or even renal failure. Of these, about half have severe renal impairment, and about half receive dialysis.

[0009] Unfortunately, kidney damage will progress despite ERT. Patients with an eGFR of 30 may deteriorate to the point of requiring dialysis within two to five years. Approximately 30% of patients receiving ERT will eventually require dialysis or a kidney transplant, depending on when ERT is started. The earlier ERT is started, the longer kidney function can be preserved, but because Fabry disease is rare and often misdiagnosed, the start of ERT may be delayed.

[0010] Furthermore, and as discussed above, ERT often does not adequately penetrate the kidneys to reduce substrate accumulation, thereby allowing further damage during disease progression. In PC treatment, the kidneys are often the means by which drugs are cleared from the body, and renal impairment may affect the pharmacokinetics of the drug and / or the pharmacodynamics of the drug. Therefore, there remains a need to treat Fabry patients with renal impairment. Summary of the invention

[0011] Various aspects of the invention relate to the use of migalastat to treat Fabry patients with renal impairment and / or elevated proteinuria. Such treatment may include stabilizing the patient's renal function, reducing their left ventricular mass index (LVMi), reducing their plasma globotriaosylsphingosine (lysoGb3), and / or increasing their α-Gal A activity.

[0012] One aspect of the present invention relates to a method for treating Fabry disease in a patient with renal impairment, the method comprising administering to the patient an effective amount of migalastat or a salt thereof at a frequency of 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 a patient who has undergone ERT.

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

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

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

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

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

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

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

[0025] In one or more embodiments, administration of the migalastat or a salt thereof is effective to stabilize 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 its salt 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, the 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 6 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 present invention relates to the use of migalastat to stabilize renal function in a patient diagnosed with Fabry disease and having renal impairment. 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 a patient who has undergone ERT.

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

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

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

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

[0044] In one or more embodiments, the 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 its salt 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, the 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 6 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, administration of an effective amount of migalastat or a salt thereof to a group of patients with mild or moderate renal impairment provides a renal function of greater than -1.0 mL / min / 1.73 m 2 eGFR CKD-EPI Average annual rate of change.

[0054] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a group of patients with mild renal impairment provides a renal function of greater than -1.0 mL / min / 1.73 m 2 eGFR CKD-EPI Average annual rate of change.

[0055] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a group of patients with moderate renal impairment provides a renal function of greater than -1.0 mL / min / 1.73 m 2 eGFR CKD-EPI Average annual rate of change.

[0056] Another aspect of the present invention relates to the use of migalastat to stabilize plasma lysed Gb3 in patients diagnosed with Fabry disease and with renal impairment. 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 a patient who has undergone ERT.

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

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

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

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

[0066] In one or more embodiments, the 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 its salt 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, the 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 6 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 provides a mean reduction in plasma lyso-Gb3 of at least about 5 nmol / L after 24 months of administration of the migalastat or a salt thereof.

[0076] Another aspect of the invention relates to the use of migalastat to reduce LVMi in patients diagnosed with Fabry disease and having renal impairment. 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 a patient who has undergone ERT.

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

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

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

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

[0086] In one or more embodiments, the 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 its salt 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, the 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 6 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 a group of ERT-naive patients with moderate renal impairment provides at least about 2 g / m 2 The mean reduction in LVMi was 7.3%.

[0096] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a group of patients with moderate renal impairment who have undergone ERT provides at least about 2 g / m 2 The mean reduction in LVMi was 7.3%.

[0097] Another aspect of the invention relates to the use of migalastat to increase WBC α-Gal A activity in a patient diagnosed with Fabry disease and having renal impairment. 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 a patient who has undergone ERT.

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

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

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

[0106] In one or more embodiments, the patient's proteinuria level is greater than 1,000 mg / 24 hr prior to initiating administration of the 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 its salt 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, the 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 6 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 provides a mean increase in WBC α-Gal A activity of at least about 14 MU / hr / mg after 24 months of administration of the 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 patients with moderate renal impairment who have undergone ERT provides a mean increase in WBC α-Gal A activity of at least about 14 MU / hr / mg after 18 months of administration of the migalastat or a salt thereof.

[0117] Another aspect of the present invention relates to the use of migalastat to stabilize renal function in a patient diagnosed with Fabry disease and having elevated proteinuria. 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 a patient who has undergone ERT.

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

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

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

[0126] In one or more embodiments, the 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 its salt 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, the 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 6 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 group of patients having a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiation of administration of the migalastat or a salt thereof provides a proteinuria of greater than -2.0 mL / min / 1.73 m 2 eGFR CKD-EPI Average annual rate of change.

[0136] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a group of patients whose proteinuria level is greater than 1,000 mg / 24 hr prior to initiation of administration of the migalastat or a salt thereof provides a rate of greater than -5.0 mL / min / 1.73 m 2 eGFR CKD-EPI Average annual rate of change.

[0137] Another aspect of the present invention relates to a method for treating Fabry disease in a patient with elevated proteinuria, the method comprising administering to the patient an effective amount of migalastat or a salt thereof at a frequency of 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 a patient who has undergone ERT.

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

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

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

[0146] In one or more embodiments, the 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 its salt 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, the 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 6 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 group of patients having a proteinuria level of 100 to 1,000 mg / 24 hr prior to initiation of administration of the migalastat or a salt thereof provides a proteinuria of greater than -2.0 mL / min / 1.73 m 2 eGFR CKD-EPI Average annual rate of change.

[0156] In one or more embodiments, administration of an effective amount of migalastat or a salt thereof to a group of patients whose proteinuria level is greater than 1,000 mg / 24 hr prior to initiation of administration of the migalastat or a salt thereof provides a rate of greater than -5.0 mL / min / 1.73 m 2 eGFR CKD-EPI Average annual rate of change.

[0157] Different embodiments are listed below. It should be understood that the embodiments listed below can be combined not only as listed below, but also in other suitable combinations according to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0158] Figure 1A Shows the CL CR Changing plasma concentrations of migalastat in patients with varying degrees of renal impairment;

[0159] Figure 1B Plasma concentrations of migalastat in patients with varying degrees of renal impairment are shown as a function of time after dosing;

[0160] Figure 1C The area under the curve (AUC) for patients with different degrees of renal impairment is shown;

[0161] Figure 2 Migalastat concentrations over time in patients with moderate to severe renal impairment are shown;

[0162] Figure 3 The AUC after 48 hours in patients with varying degrees of renal impairment is shown0-∞ and correlation between migalastat concentrations;

[0163] Figure 4 The results show that the eGFR MDRD changing plasma migalastat concentrations in Fabry patients with varying degrees of renal impairment and in two Fabry patients with renal impairment;

[0164] Figure 5 Plasma AUCs are shown for patients without Fabry with varying degrees of renal impairment and for two Fabry patients with renal impairment. 0-∞ ;

[0165] Figures 6A-6D Simulated median and observed migalastat concentrations versus time for subjects with normal, severe, mild, and moderate renal impairment are shown, respectively;

[0166] Figures 7A-7D Simulated C values ​​for subjects with normal, mild, moderate, and severe renal impairment are shown. max , AUC, C min and C 48 ;

[0167] Figures 8A-8D Steady-state predictions of QOD for subjects with normal, severe, mild, and moderate renal impairment are shown, respectively;

[0168] Figures 9A-9D The C values ​​of subjects with normal, mild, moderate, and severe renal impairment are shown. max , AUC, C min and C 48 ;

[0169] Figures 10A-10B The study designs of two studies investigating the use of migalastat in Fabry patients are shown;

[0170] Fig.11 eGFR is shown for Fabry patients with normal renal function and mild and moderate renal impairment receiving migalastat therapy CKD-EPI The annual rate of change;

[0171] Figures 12A-12B eGFR is shown for Fabry patients with normal renal function and renal impairment receiving migalastat therapy and ERT, respectively CKD-EPI and mGFR 碘海醇 The annual rate of change;

[0172] Fig.13 eGFR is shown for Fabry patients with normal renal function and mild and moderate renal impairment receiving migalastat therapy and ERT CKD-EPI The annual rate of change;

[0173] Figures 14A-14E shows the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1); and

[0174] Fig.15 The wild-type GLA protein (SEQ ID NO: 2) is shown. DETAILED DESCRIPTION

[0175] Before describing several exemplary embodiments of the present invention, it should be understood that the present invention is not limited to the details of construction or method steps listed in the following description. The present invention is capable of other embodiments and can be implemented or carried out in different ways.

[0176] It has been surprisingly found that in Fabry patients with mild and moderate renal impairment, migalastat therapy stabilizes renal function, reduces LVMi, reduces plasma hemolytic Gb3 and increases WBC α-Gal A activity. Therefore, different aspects of the present invention relate to specific dosing regimens for migalastat in Fabry patients with renal impairment. Migalastat is a pharmacological partner used to treat Fabry disease. This pharmacological partner is usually cleared from the body by the kidneys. However, patients with renal impairment (a common problem for Fabry patients) may not be able to clear migalastat from the body, and it was previously unknown how patients with both Fabry disease and renal impairment respond to migalastat therapy. Because pharmacological partners are also inhibitors, it is difficult to balance the enzyme enhancing and inhibitory effects of pharmacological partners such as migalastat. In addition, due to the complex interaction between Fabry disease and renal function and the lack of understanding of the role of pharmacological partners, it is difficult to determine the dosing of migalastat in Fabry patients with renal impairment without significant clinical data and / or computer modeling.

[0177] Thus, aspects of the invention relate to methods of using migalastat or a salt thereof to treat Fabry patients with renal impairment and / or elevated proteinuria, for example by stabilizing the patient's renal function, reducing their LVMi, reducing their plasma lysosomal Gb3, and / or increasing their α-Gal A activity.

[0178] In one or more 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. The patient may have mild, moderate or severe renal impairment. In one or more embodiments, the patient has mild or moderate renal impairment. In specific embodiments, the patient has mild renal impairment. In other specific embodiments, the patient has moderate renal impairment.

[0179] definition

[0180] The terms used in this specification generally have their ordinary meanings in the art in the context of the present invention and in the specific context in which each term is used. Certain terms are discussed below or elsewhere in this specification to provide practitioners with additional guidance in describing the compositions and methods of the present invention and how to make and use them.

[0181] The term "Fabry disease" refers to an X-linked inborn error of glycosphingolipid catabolism due to a lack of lysosomal α-Gal A activity. This defect results in the accumulation of the substrate globotriaosylceramide ("GL-3", also known as Gb3 or ceramide hexasyltransferase) and related glycosphingolipids in endothelial lysosomes of the heart, kidney, skin, and other tissues. Another substrate for the enzyme is plasma globotriaosylceramide ("plasma lysoGb3").

[0182] A "carrier" is a female who has one X chromosome with a defective α-Gal A gene and one X chromosome with a normal gene, and in whom the normal allele is inactivated in one or more cell types. Carriers are usually diagnosed as having Fabry disease.

[0183] "Patient" refers to a subject who has been diagnosed as having or is suspected of having a particular disease. A patient can be a human or an animal.

[0184] A "Fabry patient" is an individual who has been diagnosed with or is suspected of having Fabry disease and has a mutated α-Gal A as further defined below. The characteristic markers of Fabry disease occur with equal frequency in male hemizygotes and female carriers, but females are generally less severely affected.

[0185] The term "ERT-naive patients" refers to Fabry patients who have never received ERT or have not received ERT for at least 6 months before starting migalastat therapy.

[0186] The term "patient who has undergone ERT" refers to a Fabry patient who received ERT just prior to starting migalastat therapy. In some embodiments, the patient who has undergone ERT has received ERT for at least 12 months just prior to starting migalastat therapy.

[0187] 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 in GenBank Accession No. X14448.1 and is shown in SEQ ID NOs: 1 and Figures 14A-14E The human α-Gal A enzyme consists of 429 amino acids and is available in GenBank accession numbers X14448.1 and U78027.1 and is shown in SEQ ID NOs: 2 and Fig.15middle.

[0188] The term "mutant protein" includes proteins with mutations in the gene encoding the protein, which causes the protein to be unable to reach a stable conformation under conditions normally present in the ER. Failure to reach a stable conformation causes a large amount of the enzyme to be degraded rather than transported to the lysosome. Such a mutation is sometimes referred to as a "conformational mutant". Such mutations include, but are not limited to, missense mutations and small in-frame deletions and insertions.

[0189] As used herein in one embodiment, the term "mutant α-Gal A" includes α-Gal A having a mutation in the gene encoding α-Gal A, which mutation results in the enzyme being unable to achieve a stable conformation under conditions normally present in the ER. The inability to achieve a stable conformation results in a large amount of the enzyme being degraded rather than being transported to the lysosome.

[0190] 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) enhances the formation of a stable molecular conformation of the protein; (ii) induces the transport of the protein from the ER to another cellular location (preferably the native cellular location), i.e., prevents ER-associated degradation of the protein; (iii) prevents aggregation of misfolded proteins; and / or (iv) restores or enhances at least part of the wild-type function and / or activity of the protein. A compound that specifically binds to, for example, α-Gal A means that it binds to the enzyme and exerts a chaperone effect on the enzyme rather than a group of related or unrelated enzymes. More specifically, this term does not refer to endogenous chaperones such as BiP, or to nonspecific reagents such as glycerol, DMSO or deuterated water, i.e., chemical chaperones, that exhibit nonspecific chaperone activity on different proteins. In one or more embodiments of the present invention, the PC may be a reversible competitive inhibitor.

[0191] A "competitive inhibitor" of an enzyme may refer to a compound that is structurally similar to the chemical structure and molecular geometry of the enzyme substrate to bind to the enzyme at approximately the same position as the substrate. Thus, the inhibitor competes with the substrate molecules for the same active site, thereby increasing the Km. Competitive inhibition is generally reversible, i.e., the competitive inhibitor can bind reversibly, if sufficient substrate molecules are available to displace the inhibitor. Thus, the amount of enzyme inhibition depends on the inhibitor concentration, the substrate concentration, and the relative affinities of the inhibitor and substrate for the active site.

[0192] As used herein, the term "specifically binds" refers to the interaction of a pharmacological chaperone with a protein, such as α-Gal A, particularly with the amino acid residues of the protein that are directly involved in contacting the pharmacological chaperone. The pharmacological chaperone specifically binds to a target protein (e.g., α-Gal A) to exert a chaperone effect on the protein rather than a group of related or unrelated proteins. The amino acid residues of the protein that interact with any given pharmacological chaperone may or may not be within the "active site" of the protein. Specific binding can be assessed by conventional binding assays or by structural studies (e.g., cocrystallization, NMR, etc.). The active site of α-Gal A is the substrate binding site.

[0193] "Defective α-Gal A activity" refers to α-Gal A activity in cells from a patient that is below the normal range compared to the activity in a normal individual (using the same method) who does not have or is not suspected of having Fabry or any other disease, particularly a hematological disease.

[0194] As used herein, the term "enhancing α-Gal A activity" or "increasing α-Gal A activity" refers to increasing the amount of α-Gal A that adopts a stable conformation in a cell that is in contact with a pharmacological partner specific for α-Gal A relative to the amount in a cell that is not in contact with a pharmacological partner specific for α-Gal A (preferably the same cell type or the same cell, for example, at an earlier time). This term also refers to increasing the transport of α-Gal A to lysosomes in a cell that is in contact with a pharmacological partner specific for α-Gal A relative to the transport of α-Gal A in the absence of contact with a pharmacological partner specific for the protein. These terms refer to both wild-type and mutant α-Gal A. In one embodiment, the increase in the amount of α-Gal A in the cell is measured by measuring the hydrolysis of an artificial substrate in a lysate from cells that have been treated with PC. An increase in hydrolysis indicates an increase in α-Gal A activity.

[0195] The term "α-Gal A activity" refers to the normal physiological function of wild-type α-Gal A in cells. For example, α-Gal A activity includes the hydrolysis of GL-3.

[0196] A "responder" is an individual diagnosed with or suspected of having a lysosomal storage disorder (e.g., such as Fabry disease) whose cells exhibit sufficiently increased α-Gal A activity and / or a reduction in symptoms or enhancement of surrogate markers, respectively, in response to exposure to PC. Non-limiting examples of enhancement of Fabry surrogate markers are those disclosed in LysoGb3 and U.S. Patent Application Publication No. US2010 / 0113517, which is hereby incorporated by reference in its entirety.

[0197] Non-limiting examples of improvements in surrogate markers of Fabry disease disclosed in US2010 / 0113517 include increases in α-Gal A levels or activity in cells (e.g., fibroblasts) and tissues; decreases in GL-3 accumulation; decreases in plasma concentrations of homocysteine ​​and vascular cell adhesion molecule-1 (VCAM-1); decreases in GL-3 accumulation in cardiomyocytes and valvular fibroblasts; decreases in plasma lysoGb3; decreases in cardiac hypertrophy (particularly left ventricular hypertrophy), improvements in valvular dysfunction and arrhythmias; improvements in proteinuria; decreases in urine concentrations of lipids such as CTH, lactosylceramide, ceramide, and increases in urine concentrations of glucosylceramide and sphingomyelin; absence of lamellar inclusions (zebra bodies) in glomerular epithelial cells; improvements in renal function; reduction in hypohidrosis; absence of angiokeratoma; and improvements in hearing abnormalities such as high-frequency sensorineural hearing loss, progressive hearing loss, sudden deafness, or tinnitus. Improvement of neurological symptoms includes prevention of transient ischemic attack (TIA) or stroke; and improvement of neuropathic pain that manifests itself as paresthesias of the extremities (burning or tingling in the extremities). Another type of clinical marker that can be assessed for Fabry disease is the incidence of adverse cardiovascular manifestations. Common cardiac-related signs and symptoms of 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, congestive heart failure.

[0198] As used herein, the phrase "stabilizing renal function" and similar terms refer, inter alia, to reducing the decline in renal function and / or restoring renal function. Since renal function in untreated Fabry patients is expected to decline significantly, an improvement in the rate of deterioration of renal function and / or an improvement in renal function demonstrates the benefit of migalastat therapy as described herein. Specifically, regardless of the severity of renal function and whether ERT-naive or ERT-experienced, stabilizing renal function can be manifested in Fabry patients as improving renal function or delaying the rate of deterioration of renal function when compared to similar patients not treated with the therapy of the invention, e.g., up to 0.2 mL / min / 1.73 m for one specific patient population. 2. The advantage of the treatment methods disclosed herein is that Fabry patients treated with the present invention show less or no decline in his or her renal function compared to untreated (no partner or ERT treatment) or ERT treatment. For example, improvements may be observed initially with ERT treatment, but after the first two or three years of therapy, patients treated with ERT experience a sharp decline in renal function, similar to the degree of decline observed before ERT treatment. In contrast, the therapy described herein is more effective in clearing lysosomal GL-3, and has been shown to cause improvements in patients who are not expected to improve (e.g., in patients who have undergone ERT) (e.g., see Example 5). So far, even after two years after treatment, clinical data using the therapy described herein are expected to continue to improve the prognosis of patients. Therefore, in some embodiments, patients treated with the therapy described herein continue to stabilize renal function for more than two years after treatment (e.g., by improving the patient's glomerular filtration rate (GFR) or delaying the rate of decline of its GFR).

[0199] Renal impairment refers to a patient with a GFR less than 90 mL / min / 1.73 m 2 The two most commonly used equations for calculating estimated glomerular filtration rate (eGFR) from serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the Modification of Diet in Renal Disease (MDRD), which are referred to as eGFR CKD-EPI and eGFR MDRD The severity of chronic kidney disease has been defined in six stages: a. (Stage 0) Normal renal function - GFR greater than 90 mL / min / 1.73 m 2 and no proteinuria; b. (Stage 1) - GFR greater than 90 mL / min / 1.73 m 2 and there is evidence of kidney damage; c. (Stage 2) (mild) - GFR 60 to 89 mL / min / 1.73 m 2 and there is evidence of kidney damage; d. (Stage 3) (Moderate) - GFR 30 to 59 mL / min / 1.73 m 2 ; e. (Stage 4) (Severe) - GFR 15 to 29 mL / min / 1.73 m 2 ; f. (Stage 5) Renal failure - GFR less than 15 mL / min / 1.73 m 2 .

[0200] "Elevated proteinuria" means that the urine protein level is above the normal range. The normal range of urine protein is 0-150 mg per day, so elevated proteinuria is a urine protein level of about 150 mg per day.

[0201] As used herein, the phrase "stabilizing plasma lysoGb3" and similar terms refer to reducing an increase in plasma lysoGb3 and / or reducing plasma lysoGb3. Since plasma lysoGb3 is expected to increase significantly in untreated Fabry patients, an improvement in the rate of plasma lysoGb3 accumulation and / or an improvement in plasma lysoGb3 demonstrates the benefit of migalastat therapy as described herein.

[0202] A dose that achieves one or more of the above-described responses is a "therapeutically effective dose."

[0203] The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and generally do not produce adverse reactions when administered to humans. In certain embodiments, as used herein, the term "pharmaceutically acceptable" refers to approved by a federal or state government regulatory agency or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopeias for use in animals, more particularly in humans. The term "carrier" in terms of a pharmaceutical carrier refers to a diluent, adjuvant, excipient or vehicle that is administered with a compound. Such pharmaceutical carriers can be sterile liquids, such as water and oils. Preferably, water or aqueous saline solutions and dextrose and glycerol aqueous solutions are used as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" edited by EW Martin, the 18th edition or other versions.

[0204] The term "enzyme replacement therapy" or "ERT" refers to the introduction of a non-natural, purified enzyme into an individual who lacks such an enzyme. The protein administered can 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 into an individual who would otherwise need or benefit from the administration of a purified enzyme, e.g., the individual suffers from an enzyme deficiency. The introduced enzyme can be a purified recombinant enzyme produced in vitro, or a protein purified from an isolated tissue or fluid (such as, for example, the placenta or animal milk) or from a plant.

[0205] As used herein, the term "isolated" means that the reference material is removed from the environment in which it is usually found. Therefore, the isolated biological material may not contain cellular components, i.e., components of the cells in which the material is found or produced. In the case of nucleic acid molecules, the isolated nucleic acid includes PCR products, mRNA bands on gels, cDNA or restriction fragments. In another embodiment, the isolated nucleic acid is preferably excised from the chromosome in which it can be found, and more preferably no longer connected to the non-regulatory non-coding region, or connected to other genes upstream or downstream of the gene contained by the isolated nucleic acid molecule when found in the chromosome. In another embodiment, the isolated nucleic acid lacks one or more introns. The isolated nucleic acid includes sequences inserted into plasmids, cosmids, artificial chromosomes, etc. Therefore, in a specific embodiment, the recombinant nucleic acid is an isolated nucleic acid. The isolated protein can be combined with other proteins or nucleic acids or both combined with it in the cell, or if it is a membrane-bound protein, it is combined with the cell membrane. The isolated organelle, cell or tissue is removed from the anatomical site found in the organism. The isolated material can be but need not be purified.

[0206] The terms "about" and "approximately" generally mean an acceptable degree of error for a quantity measured given the nature or precision of a given measurement. Typical exemplary degrees of error are within 20%, 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" may mean values ​​within an order of magnitude, preferably within 10 or 5 times, and more preferably within 2 times of a given value. Unless otherwise indicated, numerical quantities given herein are approximate, meaning that when not explicitly stated, the terms "about" or "approximately" may be inferred.

[0207] 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" means an amount of migalastat free base, or an equivalent amount of migalastat free base provided by a salt of migalastat. For example, due to the weight of the hydrochloride salt, 150 mg of migalastat hydrochloride provides only as much 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.

[0208] Unless specifically stated to the contrary, the term "migalastat" encompasses migalastat free base or a pharmaceutically acceptable salt thereof (eg, migalastat HCl).

[0209] Fabry disease

[0210] Fabry disease is a rare, progressive and destructive X-linked lysosomal storage disorder. Mutations in the GLA gene result in a deficiency of the lysosomal enzyme α-Gal A, which is required for glycosphingolipid metabolism. From the early days of life, the reduction in α-Gal A activity results in the accumulation of glycosphingolipids (including GL-3 and plasma hemolysis Gb3), and causes the symptoms and life-limiting sequelae of Fabry disease, including pain, gastrointestinal symptoms, renal failure, cardiomyopathy, cerebrovascular events and early death. Early onset therapy and lifelong treatment provide the opportunity to slow down disease progression and extend life expectancy.

[0211] Fabry disease encompasses a wide range of disease severity and age of onset, although it has traditionally been divided into 2 major phenotypes, "classic" and "late-onset." The classic phenotype has been primarily attributed to males with undetectable to low α-Gal A activity and earlier onset of renal, cardiac, and / or cerebrovascular manifestations. The late-onset phenotype has been primarily attributed to males with higher residual α-Gal A activity and later onset of these disease manifestations. Heterozygous female carriers typically express the late-onset phenotype, but may also display the classic phenotype depending on the pattern of X chromosome inactivation.

[0212] More than 800 GLA mutations that cause Fabry disease have been identified. Approximately 60% are missense mutations, resulting in single amino acid substitutions in the α-GalA enzyme. Missense GLA mutations typically result in the production of abnormally folded and unstable forms of α-Gal A, and most are associated with the classical phenotype. Normal cellular quality control mechanisms in the endoplasmic reticulum block the transport of these abnormal proteins to lysosomes and target them for premature degradation and elimination. Many missense mutant forms are targets of migalastat, a specific pharmacological chaperone for α-Gal A.

[0213] The clinical manifestations of Fabry disease have a wide range of severity and are roughly related to the residual α-GAL levels of the patient. Most of the patients currently treated are called classic Fabry disease patients, most of whom are male. These patients experience diseases of various organs (including kidneys, heart and brain), where symptoms of the disease first appear in adolescence, and usually the severity continues to progress until death in the fourth or fifth decade of life. Many recent studies have shown that there are a large number of undiagnosed men and women who have a series of Fabry disease symptoms that usually appear for the first time in adulthood, such as impaired heart or kidney function and stroke. Individuals with this type of Fabry disease (called late-onset Fabry disease) tend to have higher residual α-GAL levels compared to patients with classic Fabry disease. Individuals with late-onset Fabry disease usually experience disease symptoms for the first time in adulthood, and disease symptoms are usually concentrated in a single organ, such as enlargement of the left ventricle or progressive renal failure. In addition, late-onset Fabry disease may also appear in the form of stroke of unknown cause.

[0214] Fabry patients have progressive renal damage, and untreated patients show end-stage renal damage before the fifth decade of life. The lack of α-Gal A activity causes GL-3 and related glycosphingolipids to accumulate in many cell types, including cells in the kidney. GL-3 accumulates in podocytes, epithelial cells, and tubular cells of the distal tubules and loops of Henle. Renal impairment can be manifested as proteinuria and decreased glomerular filtration rate.

[0215] Because Fabry disease can lead to progressive deterioration of renal function, understanding the pharmacokinetics (PK) of potential therapeutic agents in individuals with renal impairment is important, particularly for therapeutic agents that are primarily eliminated by renal excretion. Impaired renal function can result in accumulation of therapeutic agents to toxic levels.

[0216] Because Fabry disease is rare, involves multiple organs, has a wide age range of onset, and is heterogeneous, correct diagnosis is a challenge. Awareness among healthcare professionals is low, and misdiagnosis is frequent. Once a patient has symptoms, coupled with mutation analysis, the diagnosis of Fabry disease is most often confirmed based on reduced α-Gal A activity in plasma or peripheral white blood cells (WBC). In women, diagnosis is even more challenging because enzyme identification in carrier women is less reliable due to random X chromosome inactivation in some cells of the carrier. For example, some affirmative carriers (daughters of males affected by the classic type) have α-Gal A enzyme activity ranging from normal to very low activity. Since carriers can have normal α-Gal A enzyme activity in white blood cells, identification of α-Gal A mutations by genetic testing alone provides accurate carrier identification and / or diagnosis.

[0217] Mutated forms of α-galactosidase A that are considered amenable to migalastat are defined as showing a ≥1.20-fold relative increase (+10 μM migalastat) and an absolute increase (+10 μM migalastat) of ≥3.0% of wild-type in an in vitro assay validated according to Good Laboratory Practice (GLP HEK or Migalastat Amenability Assay) when the mutant forms of α-galactosidase A are expressed in HEK-293 cells (referred to as the "HEK assay"). Such mutations are also referred to herein as "HEK assay amenability" mutations.

[0218] Previous screening methods have been provided that assess enzyme enhancement before starting treatment. For example, assays using HEK-293 cells have been used in clinical trials to predict whether a given mutation responds to treatment with a pharmacological partner (e.g., migalastat). In this assay, a cDNA construct was established. The corresponding α-Gal A mutant form was transiently expressed in HEK-293 cells. The cells were then incubated with migalastat (17nM to 1mM) for 4 to 5 days. Afterwards, α-Gal A levels were measured in cell lysates using a synthetic fluorescent substrate (4-MU-α-Gal) or by Western blotting. This has been performed for missense or small in-frame insertion / deletion mutations known to cause disease. Mutations previously identified as responding to PC (e.g., migalastat) using these methods are listed in U.S. Patent No. 8,592,362, which is hereby incorporated by reference in its entirety.

[0219] Pharmacological partners

[0220] Binding of small molecule inhibitors of LSD-related enzymes can increase the stability of mutant enzymes and corresponding wild-type enzymes (see U.S. Pat. Nos. 6,274,597; 6,583,158; 6,589,964; 6,599,919; 6,916,829 and 7,141,582, all of which are incorporated herein by reference). In particular, administration of small molecule derivatives of glucose and galactose, which are specific, selective, competitive inhibitors of several target lysosomal enzymes, effectively increased the stability of the enzymes in cells in vitro and, thus, increased the trafficking of the enzymes to the lysosomes. Thus, by increasing the amount of enzyme in the lysosomes, the hydrolysis of the enzyme substrate is expected to increase. The original theory behind this strategy is as follows: because the mutant enzyme protein is unstable in the ER (Ishii et al., Biochem. Biophys. Res. Comm. [Biochemistry and Biophysics Research Communications] 1996; 220: 812-815), the enzyme protein is blocked in the normal transport pathway (ER→Golgi apparatus→endosome→lysosome) and degraded prematurely. Therefore, compounds that bind to the mutant enzyme and increase its stability can act as a "chaperone" for the enzyme and increase the amount that can leave the ER and move to the lysosome. In addition, since the folding and transport of some wild-type proteins is incomplete, and in some cases, up to 70% of some wild-type proteins are degraded before reaching their final cellular location, these chaperones can be used to stabilize the wild-type enzyme and increase the amount of enzyme that can leave the ER and be transported to the lysosome.

[0221] In one or more embodiments, the pharmacological partner comprises migalastat or a salt thereof. The compound migalastat (also known as 1-deoxygalactonojirimycin (1-DGJ) or (2R,3S,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol) is a compound having the following chemical formula:

[0222] 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 is adjusted so that the dosage of migalastat received by the patient is comparable to the amount received when migalastat free base is used. An example of a pharmaceutically acceptable salt of migalastat is migalastat HCl:

[0223] Migalastat is a low molecular weight iminosugar and an analog of the terminal galactose of GL-3. In vitro and in vivo pharmacology studies have demonstrated that migalastat acts as a pharmacological chaperone, selectively and reversibly binding with high affinity to the active site of wild-type α-Gal A and specific mutant forms of α-Gal A, whose genotypes are referred to as HEK assay amenable mutations. Migalastat binding stabilizes these mutant forms of α-Gal A in the endoplasmic reticulum, thereby facilitating their proper trafficking to lysosomes, where dissociation of migalastat allows α-Gal A to reduce the levels of GL-3 and other substrates. Approximately 30%-50% of patients with Fabry disease have HEK assay amenable mutations; the majority of which are associated with the classic phenotype of the disease. A list of HEK assay amenable mutations includes at least those mutations listed in Table 1 below. In one or more embodiments, if the double mutation is present on the same chromosome (males and females), the patient is considered HEK assay compliant if the double mutation is present in one entry in Table 1 (e.g., D55V / Q57L). In some embodiments, if the double mutation is present on different chromosomes (only in females), the patient is considered HEK assay compliant if either of the individual mutations is present in Table 1. In addition to Table 1 below, GALAFOLD may also be used in approved TM GALAFOLD in various countries TM HEK assay amenability mutations may be found in the Summary of Product Characteristics and / or Prescribing Information or on the website www.galafoldamenabilitytable.com, each of which is hereby incorporated by reference in its entirety. Table 1 Nucleotide changes Nucleotide changes Protein sequence changes c.7C>G c.C7G L3V c.8T>C c.T8C L3P c.[11G>T;620A>C] c.G11T / A620C R4M / Y207S c.37G>A c.G37A A13T c.37G>C c.G37C A13P c.43G>A c.G43A A15T c.44C>G c.C44G A15G c.53T>G c.T53G F18C c.58G>C c.G58C A20P c.59C>A c.C59A A20D c.70T>C or c.70T>A c.T70C or c.T70A W24R c.70T>G c.T70G W24G c.72G>C or c.72G>T c.G72C or c.G72T W24C c.95T>C c.T95C L32P c.97G>T c.G97T D33Y c.98A>G c.A98G D33G c.100A>G c.A100G N34D c.101A>C c.A101C N34T c.101A>G c.A101G N34S c.102T>G or c.102T>A c.T102G or c.T102A N34K c.103G>C or c.103G>A c.G103C or c.G103A G35R c.104G>A c.G104A G35E c.104G>T c.G104T G35V c.107T>C c.T107C L36S c.107T>G c.T107G L36W c.108G>C or c.108G>T c.G108C or c.G108T L36F c.109G>A c.G109A A37T c.110C>T c.C110T A37V c.122C>T c.C122T T41I Table 1 Table 1 Table 1 Table 1 Table 1 Nucleotide changes Nucleotide changes Protein sequence changes c.596T>G c.T596G V199G c.599A>G c.A599G Y200C c.602C>T c.C602T S201F c.602C>A c.C602A S201Y c.608A>T c.A608T E203V c.609G>C or c.609G>T c.G609C or c.G609T E203D c.613C>A c.C613A P205T c.613C>T c.C613T P205S c.614C>T c.C614T P205L c.619T>C c.T619C Y207H c.620A>C c.A620C Y207S c.623T>G c.T623G M208R c.628C>T c.C628T P210S c.629C>T c.C629T P210L c.638A>G c.A638G K213R c.638A>T c.A638T K213M c.640C>T c.C640T P214S c.641C>T c.C641T P214L c.643A>G c.A643G N215D c.644A>G c.A644G N215S c.644A>T c.A644T N215I c.[644A>G; 937G>T] c.A644G / G937T N215S / D313Y c.646T>G c.T646G Y216D c.647A>G c.A647G Y216C c.655A>C c.A655C I219L c.656T>A c.T656A I219N c.656T>C c.T656C I219T c.659G>A c.G659A R220Q Table 1 Nucleotide changes Nucleotide changes Protein sequence changes c.659G>C c.G659C R220P c.662A>C c.A662C Q221P c.671A>C c.A671C N224T c.671A>G c.A671G N224S c.673C>G c.C673G H225D c.683A>G c.A683G N228S c.687T>A or c.687T>G c.T687A or c.T687G F229L c.695T>C c.T695C I232T c.713G>A c.G713A S238N c.716T>C c.T716C I239T c.720G>C or c.720G>T c.G720C or c.G720T K240N c.724A>G c.A724G I242V c.724A>T c.A724T I242F c.725T>A c.T725A I242N c.725T>C c.T725C I242T c.728T>G c.T728G L243W c.729G>C or c.729G>T c.G729C or c.G729T L243F c.730G>A c.G730A D244N c.730G>C c.G730C D244H c.733T>G c.T733G W245G c.740C>G c.C740G S247C c.747C>G or c.747C>A c.C747G or c.C747A N249K c.749A>C c.A749C Q250P c.749A>G c.A749G Q250R c.750G>C c.G750C Q250H c.758T>C c.T758C I253T c.758T>G c.T758G I253S c.760-762delGTT c.760_762delGTT p.V254del Table 1 Nucleotide changes Nucleotide changes Protein sequence changes c.769G>C c.G769C A257P c.770C>G c.C770G A257G c.772G>C or c.772G>A c.G772C or c.G772A G258R c.773G>T c.G773T G258V c.776C>G c.C776G P259R c.776C>T c.C776T P259L c.779G>A c.G779A G260E c.779G>C c.G779C G260A c.781G>A c.G781A G261S c.781G>C c.G781C G261R c.781G>T c.G781T G261C c.788A>G c.A788G N263S c.790G>T c.G790T D264Y c.794C>T c.C794T P265L c.800T>C c.T800C M267T c.805G>A c.G805A V269M c.806T>C c.T806C V269A c.809T>C c.T809C I270T c.810T>G c.T810G I270M c.811G>A c.G811A G271S c.[811G>A;937G>T] c.G811A / G937T G271S / D313Y c.812G>A c.G812A G271D c.823C>G c.C823G L275V c.827G>A c.G827A S276N c.829T>G c.T829G W277G c.831G>T or c.831G>C c.G831T or c.G831C W277C c.832A>T c.A832T N278Y c.835C>G c.C835G Q279E Table 1 Table 1 Nucleotide changes Nucleotide changes Protein sequence changes c.902G>A c.G902A R301Q c.902G>T c.G902T R301L c.907A>T c.A907T I303F c.908T>A c.T908A I303N c.911G>A c.G911A S304N c.911G>C c.G911C S304T c.919G>A c.G919A A307T c.922A>G c.A922G K308E c.924A>T or c.924A>C c.A924T or c.A924C K308N c.925G>C c.G925C A309P c.926C>T c.C926T A309V c.928C>T c.C928T L310F c.931C>G c.C931G L311V c.935A>G c.A935G Q312R c.936G>T or c.936G>C c.G936T or c.G936C Q312H c.937G>T c.G937T D313Y c.[937G>T; 1232G>A] c.G937T / G1232A D313Y / G411D c.938A>G c.A938G D313G c.946G>A c.G946A V316I c.947T>G c.T947G V316G c.950T>C c.T950C I317T c.955A>T c.A955T I319F c.956T>C c.T956C I319T c.959A>T c.A959T N320I c.962A>G c.A962G Q321R c.962A>T c.A962T Q321L c.963G>C or c.963G>T c.G963C or c.G963T Q321H c.964G>A c.G964A D322N Table 1 Nucleotide changes Nucleotide changes Protein sequence changes c.964G>C c.G964C D322H c.966C>A or c.966C>G c.C966A or c.C966G D322E c.968C>G c.C968G P323R c.973G>A c.G973A G325S c.973G>C c.G973C G325R c.978G>C or c.978G>T c.G978C or c.G978T K326N c.979C>G c.C979G Q327E c.980A>T c.A980T Q327L c.983G>C c.G983C G328A c.989A>G c.A989G Q330R c.1001G>A c.G1001A G334E c.1010T>C c.T1010C F337S c.1012G>A c.G1012A E338K c.1016T>A c.T1016A V339E c.1027C>A c.C1027A P343T c.1028C>T c.C1028T P343L c.1033T>C c.T1033C S345P c.1046G>C c.G1046C W349S c.1055C>G c.C1055G A352G c.1055C>T c.C1055T A352V c.1061T>A c.T1061A I354K c.1066C>G c.C1066G R356G c.1066C>T c.C1066T R356W c.1067G>A c.G1067A R356Q c.1067G>C c.G1067C R356P c.1072G>C c.G1072C E358Q c.1073A>C c.A1073C E358A c.1073A>G c.A1073G E358G Table 1 Nucleotide changes Nucleotide changes Protein sequence changes c.1074G>T or c.1074G>C c.G1074T or c.G1074C E358D c.1076T>C c.T1076C I359T c.1078G>A c.G1078A G360S c.1078G>T c.G1078T G360C c.1079G>A c.G1079A G360D c.1082G>A c.G1082A G361E c.1082G>C c.G1082C G361A c.1084C>A c.C1084A P362T c.1085C>T c.C1085T P362L c.1087C>T c.C1087T R363C c.1088G>A c.G1088A R363H c.1102G>A c.G1102A A368T c.1117G>A c.G1117A G373S c.1124G>A c.G1124A G375E c.1153A>G c.A1153G T385A c.1168G>A c.G1168A V390M c.1172A>C c.A1172C K391T c.1184G>A c.G1184A G395E c.1184G>C c.G1184C G395A c.1192G>A c.G1192A E398K c.1202_1203insGACTTC c.1202_1203insGACTTC p.T400_S401dup c.1208T>C c.T1208C L403S c.1225C>G c.C1225G P409A c.1225C>T c.C1225T P409S c.1225C>A c.C1225A P409T c.1228A>G c.A1228G T410A c.1229C>T c.C1229T T410I c.1232G>A c.G1232A G411D Table 1 Nucleotide changes Nucleotide changes Protein sequence changes c.1235C>A c.C1235A T412N c.1253A>G c.A1253G E418G c.1261A>G c.A1261G M421V

[0224] Renal function in Fabry patients

[0225] Progressive decline in renal function is a major complication of Fabry disease. For example, patients with the classic Fabry phenotype exhibit progressive renal impairment that may ultimately require dialysis or renal transplantation.

[0226] A commonly used method in the art for assessing renal function is GFR. Typically, GFR is the volume of fluid filtered from the glomerular capillaries into the Bowman's capsule per unit time. Clinically, GFR is estimated based on the clearance of creatinine in serum. GFR can be estimated by collecting urine to determine the amount of creatinine removed from the blood over a given time interval. Age, body size, and sex are also taken into account. The lower the GFR number, the more severe the kidney damage.

[0227] Some studies have shown that untreated Fabry patients experience GFR changes between 7.0 and 18.9 mL / min / 1.73 m 2Patients receiving ERT may experience a mean decline in GFR between 2.0 and 2.7 mL / min / 1.73 m 2 The average decline was 2.3% between 2009 and 2011, although patients with more pronounced proteinuria or more severe chronic kidney disease may decline more rapidly.

[0228] Estimated GFR (eGFR) is calculated from serum creatinine using an isotope dilution mass spectrometry (IDMS) traceable equation. The two most commonly used equations for estimating glomerular filtration rate (GFR) from serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and the Modification of Diet in Renal Disease (MDRD) study equation. Both the MDRD study and the CKD-EPI equation include variables for age, sex, and race, which can allow providers to observe the presence of CKD even if the serum creatinine concentration appears to be within or slightly above the normal reference interval.

[0229] The CKD-EPI equation uses a 2-slope "spline" 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 年龄 ×1.018 [if female] ×1.159 [if black] in: S cr is serum creatinine in mg / dL, The κ for females is 0.7 and for males is 0.9, The α for females was -0.329 and for males was -0.411, min means S cr / κ is the minimum value or 1, and max represents S cr / κ is the maximum value or 1.

[0230] The following is the IDMS traceable MDRD study equation (for the creatinine method calibrated relative to the IDMS reference method): GFR (mL / min / 1.73m 2 )=175×(S cr ) -1.154 ×(age) -0.203 ×(0.742 if female) ×(1.212 if African American)

[0231] The equation does not require weight or height variables as these results are reported normalized to 1.73m 2This equation has been used to calculate the body surface area of ​​an adult with impaired renal function (eGFR < 60 mL / min / 1.73 m 2 ) has been extensively validated in Caucasian and African American populations and has shown good performance in patients with all common etiologies of renal disease.

[0232] To estimate creatinine clearance (eC Cr ) is to use the Cockcroft-Gault equation, which in turn estimates GFR in mL / min: Creatinine clearance (mL / min) = [(140-age) x weight (Kg)*] ÷ 72 x serum creatinine (mg / dL) [*If female, multiply by 0.85]

[0233] The Cockcroft-Gault equation is the equation recommended by the U.S. Food and Drug Administration for use in renal impairment studies. The creatinine clearance calculated using the Cockcroft-Gault equation is usually relative to 1.73 m 2 Therefore, this equation can be expressed in mL / min / 1.73m 2 The normal range of GFR (adjusted for body surface area) is 100-130 mL / min / 1.73 m2 in men younger than 40 years old. 2 and 90-120 mL / min / 1.73 m in women under 40 years old 2 .

[0234] The severity of chronic kidney disease has been defined in six stages (see also Table 2): (Stage 0) Normal renal function - GFR greater than 90 mL / min / 1.73 m 2 and no proteinuria; (Stage 1) - GFR greater than 90 mL / min / 1.73 m 2 and evidence of renal impairment; (Stage 2) (Mild) - GFR 60 to 89 mL / min / 1.73 m 2 and evidence of renal impairment; (Stage 3) (Moderate) - GFR 30 to 59 mL / min / 1.73 m 2 (Stage 4) (Severe) - GFR is 15 to 29 mL / min / 1.73 m 2 (Stage 5) Renal failure - GFR less than 15 mL / min / 1.73 m 2 Table 2 below shows the various kidney disease stages and corresponding GFR levels. Table 2

[0235] Dosage, Formulation and Administration

[0236] One or more dosing regimens described herein are particularly suitable for Fabry patients with a certain degree of renal impairment. Several studies have investigated the use of 150 mg migalastat hydrochloride every other day (QOD) in Fabry patients. One study was a 24-month trial in 67 ERT-naive patients, including a 6-month double-blind, placebo-controlled period. The other study was an active-controlled, 18-month trial in 57 patients who had undergone ERT, with a 12-month open-label extension period (OLE). Both studies included patients with an estimated glomerular filtration rate (eGFR) ≥ 30 mL / min / 1.73 m 2 Therefore, both studies included Fabry patients with normal renal function as well as patients with mild and moderate renal impairment, but neither study included patients with severe renal impairment.

[0237] Studies of migalastat treatment in Fabry patients determined that 150 mg of migalastat hydrochloride every other day slowed disease progression as measured by surrogate markers.

[0238] Thus, in one or more embodiments, migalastat or a salt thereof is administered to Fabry patients at a frequency of once every other day (also referred to as "QOD"). In various embodiments, the doses described herein relate to migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof that is not the hydrochloride. 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."

[0239] An effective amount of migalastat or a salt thereof can be in the range of about 100 mg FBE to about 150 mg FBE. Exemplary dosages 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.

[0240] Again, it should be noted that 150 mg of migalastat HCl is equivalent to 123 mg of migalastat in free base form. Therefore, in one or more embodiments, the dose is 150 mg of migalastat HCl or an equivalent dose of migalastat or a salt thereof that is not the HCl salt, administered at a frequency of once every other day. As described above, this dose is referred to as 123 mg FBE of migalastat. In other embodiments, the dose is 150 mg of migalastat HCl administered at a frequency of once every other day. In other embodiments, the dose is 123 mg of migalastat free base administered at a frequency of once every other day.

[0241] 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.

[0242] Thus, in various embodiments, migalastat therapy comprises administering 123 mg FBE every other day, such as administering 150 mg of migalastat HCl every other day.

[0243] The administration of migalastat or its salt can be continued for a certain period of time. In one or more embodiments, migalastat or its salt is administered for a duration of at least 28 days, for example at least 30, 60 or 90 days, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 20, 24, 30 or 36 months, or at least 1, 2, 3, 4 or 5 years. In different embodiments, migalastat therapy is a long-term migalastat therapy of 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).

[0244] The administration of migalastat or its salt according to the present invention can be in the form of a formulation suitable for any administration route, but is preferably administered in an oral dosage form (e.g., tablets, capsules or solutions). As an example, capsules are orally administered to a patient, each capsule containing 150 mg of migalastat hydrochloride or an equivalent dose of migalastat or its salt other than hydrochloride.

[0245] In some embodiments, PC (eg, migalastat or a salt thereof) is administered orally. In one or more embodiments, PC (eg, migalastat or a salt thereof) is administered by injection. PC may be accompanied by a pharmaceutically acceptable carrier, which may depend on the method of administration.

[0246] In one or more embodiments, PC (e.g., migalastat or a salt thereof) is administered as a monotherapy and can be in a form suitable for any route of administration, including, for example, oral administration in the form of tablets or capsules or liquids, or administration in the form of sterile aqueous solutions for injection. In other embodiments, PC is provided as a dry lyophilized powder for addition to the formulation of the replacement enzyme during or immediately after reconstitution to prevent enzyme aggregation in vitro prior to administration.

[0247] When PC (e.g., migalastat or its salt) is formulated for oral administration, tablets or capsules can be prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silicon dioxide); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be present as dry products (constituted with water or other suitable vehicles before use). Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol or fractionated vegetable oils); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). Where appropriate, the preparation may also contain buffer salts, flavoring agents, coloring agents and sweeteners. Preparations for oral administration may be suitably formulated to controllably release the active partner compound.

[0248] Pharmaceutical formulations of PC (e.g., migalastat or its salt) 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 have fluidity to the extent that it is easy to inject. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms (e.g., bacteria and fungi). The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and polyethylene glycol, etc.), a suitable mixture thereof, and a vegetable oil. Appropriate fluidity can be maintained, for example, by the use of a coating (e.g., lecithin), by maintaining the desired particle size in the case of a dispersion, and by the use of a surfactant. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, etc.). In many cases, it will be reasonable to include an isotonic agent (e.g., a sugar 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.

[0249] As required, sterile injectable solutions can be prepared by incorporating the purified enzyme (if any) and PC (e.g., migalastat or its salt) in the required amounts in an appropriate solvent with the various other ingredients listed above, followed by filtration or terminal sterilization. Typically, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and the required other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying techniques, which produce a powder of the active ingredient plus any additional desired ingredients from a previously sterile filtered solution thereof.

[0250] The formulation may contain excipients. Pharmaceutically acceptable excipients that may be included in the formulation are: buffers such as citrate buffers, phosphate buffers, acetate buffers, bicarbonate buffers, 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; polyvinylpyrrolidone; sugars such as dextran, mannitol, sorbitol, and glycerol; propylene glycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol; glycine or other amino acids; and lipids. Buffer systems used with the formulation include citrate; acetate; bicarbonate; and phosphate buffer. Phosphate buffer is a preferred embodiment.

[0251] The route of administration of the chaperone compound can be oral or parenteral, including intravenous, subcutaneous, intraarterial, intraperitoneal, intraocular, intramuscular, buccal, rectal, vaginal, intraorbital, intracerebral, intradermal, intracranial, intraspinal, intraventricular, intrathecal, intracisternal, intracapsular, intrapulmonary, intranasal, transmucosal, transdermal, or via inhalation.

[0252] Administration of the above-described parenteral formulations of the chaperone compound may be by bolus injection of periodic injections of the formulation, or may be administered by intravenous or intraperitoneal administration from a depot, which may be external (e.g., an IV bag) or internal (e.g., a bioerodible implant).

[0253] The embodiments relating to pharmaceutical formulation and administration can be combined with any 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 hemolytic Gb3 and / or methods of treating gastrointestinal symptoms (e.g., diarrhea), methods of enhancing α-GalA in patients diagnosed with or suspected of having Fabry disease, the use of a pharmacological chaperone of α-GalA in the preparation of a medicament for treating patients diagnosed with Fabry disease or a pharmacological chaperone of α-GalA for treating patients diagnosed with Fabry disease, and embodiments relating to compliance mutations, PCs, and suitable doses thereof.

[0254] In one or more embodiments, 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 by means of an infusion. This therapy has been developed for many genetic disorders, including LSDs cited above (e.g., Fabry disease). After infusion, the exogenous enzyme is expected to be absorbed by the tissue through a nonspecific or receptor-specific mechanism. Typically, the absorption efficiency is not high and the circulation time of the exogenous protein is short. In addition, the exogenous protein is unstable and undergoes rapid intracellular degradation and has the potential for an adverse immune response in the event of subsequent treatment. In one or more embodiments, the partner is administered simultaneously with the replacement enzyme (e.g., a replacement for α-Gal A). In some embodiments, the partner is co-formulated with the replacement enzyme (e.g., a replacement for α-Gal A).

[0255] In one or more embodiments, the patient is switched from ERT to migalastat therapy. In some embodiments, a patient receiving ERT is identified, the patient's ERT is interrupted, and the patient begins receiving migalastat therapy. Migalastat therapy can be performed according to any of the methods described herein.

[0256] Stable renal function

[0257] The dosing regimens described herein can stabilize renal function in Fabry patients with varying degrees of renal impairment. In one or more embodiments, about 100 mg to about 150 mg FBE of migalastat or a salt thereof is administered to Fabry patients with renal impairment at a frequency of once every other day. In one or more embodiments, 123 mg FBE of migalastat or a salt thereof, such as 123 mg of migalastat or 150 mg of migalastat hydrochloride, is administered to the patient every other day. In one or more embodiments, the patient has mild or moderate renal impairment. In specific embodiments, the patient has mild renal impairment. In other specific embodiments, the patient has moderate renal impairment. The patient may be ERT-naive or have undergone ERT.

[0258] The administration of migalastat can be continued for a certain period of time. In one or more embodiments, migalastat is administered for at least 28 days, such as 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, migalastat therapy is long-term migalastat therapy of 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).

[0259] Migalastat therapy can reduce the decline in renal function in Fabry patients compared to the same patients not treated with migalastat therapy. In one or more embodiments, migalastat therapy provides patients with an eGFR of CKD-EPI Annual rate of change, which is greater than (corrected to) -5.0 mL / min / 1.73 m 2 / year, 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 greater than 0 mL / min / 1.73m 2 / year. In one or more embodiments, migalastat therapy provides patients with mGFR 碘海醇 Annual rate of change, the annual rate of change is greater than -5.0mL / min / 1.73m 2 / year, 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 greater than 0 mL / min / 1.73m 2 / year. Thus, migalastat therapy can reduce the decline in renal function or even improve renal function in patients. These annual rates of change can be measured over a specific time period (e.g., over 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 ​​months, or 60 months).

[0260] Migalastat therapy can reduce the decline in renal function in a group of Fabry patients (e.g., a subpopulation of Fabry patients with varying degrees of renal impairment). In one or more embodiments, migalastat therapy provides eGFR reduction in Fabry patients with mild, moderate, or severe renal impairment. CKD-EPI The average annual rate of change is greater than -5.0 mL / min / 1.73 m 2 / year, 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 greater than 0 mL / min / 1.73m 2 In one or more embodiments, migalastat therapy provides mGFR in Fabry patients with mild, moderate or severe renal impairment. 碘海醇 The average annual rate of change is greater than -5.0 mL / min / 1.73 m 2 / year, 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 greater than 0 mL / min / 1.73m 2 These average annual rates of change can be measured over a specific time period (e.g., over 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 ​​months, or 60 months). Left ventricular mass

[0261] The dosing regimen 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) demonstrates LVMi of +4.07 and +8.0 g / m 2 The rate increases gradually between 1 and 2 months (Kampmann, Linhart et al. 2008; Wyatt, Henley et al. 2012; Germain, Weidemann et al. 2013). Since untreated Fabry patients typically show an increase in LVMi over time, both a decrease and maintenance of LVMi would indicate a benefit of migalastat therapy.

[0262] Migalastat therapy can reduce the increase in LVMi in Fabry patients compared to the same patient not treated with migalastat therapy. In one or more embodiments, migalastat therapy provides a patient with a change in LVMi that is less than (i.e., more negative than) 0 g / m 2 , for example, less than or equal to 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 Stated another way, in one or more embodiments, migalastat therapy provides greater than 0 g / m 2 14, 15, 16, 17, 18, 19, or 20 g / m 2 In one or more embodiments, the patient has mild or moderate renal impairment. In specific embodiments, the patient has mild renal impairment. In other specific embodiments, the patient has moderate renal impairment. The patient may be ERT-naive or have undergone ERT.

[0263] In one or more embodiments, migalastat therapy provides at least about 1 g / m2 of migalastat or a salt thereof to a group of patients who have undergone ERT after 18 months of administration. 2 In various embodiments, after 18 months of administration of migalastat or a salt thereof, a group of patients who have undergone ERT have a mean reduction of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g / m 2 .

[0264] In one or more embodiments, migalastat therapy provides at least about 1 g / m2 of migalastat to a group of patients with moderate renal impairment who have undergone ERT after 18 months of administration of migalastat or a salt thereof. 2 In various embodiments, after 18 months of administration of migalastat or a salt thereof, a group of patients who have undergone ERT have a mean reduction of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g / m 2 .

[0265] In one or more embodiments, migalastat therapy provides at least about 1 g / m2 of migalastat or a salt thereof to a group of ERT-naive patients after 24 months of administration. 2In various embodiments, after 24 months of administration of migalastat or a salt thereof, a group of ERT-naive patients has a mean reduction of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g / m 2 .

[0266] In one or more embodiments, migalastat therapy provides at least about 1 g / m2 of migalastat to a group of ERT-naive patients with moderate renal impairment after 24 months of administration of migalastat or a salt thereof. 2 In various embodiments, after 24 months of administration of migalastat or a salt thereof, a group of ERT-naive patients has a mean reduction of at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 g / m 2 .

[0267] References throughout the specification to "one embodiment," "certain embodiments," "different embodiments," "one or more embodiments," or "an embodiment" mean that the specific features, structures, materials, or characteristics described in connection with the embodiment are included in at least one embodiment of the present invention. Thus, phrases such as "in one or more embodiments," "in certain embodiments," "in different embodiments," "in an embodiment," or "in an embodiment" that appear in multiple places throughout the specification do not necessarily refer to the same embodiment of the present invention. Furthermore, in one or more embodiments, the specific features, structures, materials, or characteristics may be combined in any suitable manner.

[0268] Although the invention herein has been described with reference to specific embodiments, it should be understood that these embodiments are merely illustrative of the principles and applications of the invention. It should be clear to those skilled in the art that various modifications and variations may be made to the methods and apparatus of the invention without departing from the spirit and scope of the invention. Therefore, it is intended that the invention include modifications and variations within the scope of the appended claims and their equivalents.

[0269] Throughout this application, patents, patent applications, publications, product descriptions, and protocols are cited, the disclosures of which are incorporated herein by reference in their entireties for all purposes. Examples

[0270] Example 1: Pharmacokinetics of migalastat in ilafibritic patients with renal impairment

[0271] A clinical trial was conducted to investigate the pharmacokinetics and safety of migalastat HCl in illicit subjects with renal impairment. A single 150 mg dose of migalastat HCl was administered to subjects with mild, moderate, and severe renal impairment as well as normal renal function. eGFR was estimated by the Cockcroft-Gault equation according to the FDA renal impairment study guidance.

[0272] Volunteers were recruited into the Cockcroft-Gault creatinine clearance equation (CL CR ) calculated for renal function. Based on the estimated CL at screening CR The subjects were divided into groups using the Cockcroft-Gault equation. The following plasma migalastat PK parameters were determined by non-compartmental analysis using the AUTOMATO ® software (Pharsight Corporation, version 5.2). C max Maximum observed concentration t max Time to reach maximum concentration AUC 0-t The area under the concentration-time curve from hour 0 to the last measurable concentration was calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations. AUC 0-∞ The area under the concentration-time curve extrapolated to infinity was calculated using the following formula: AUC0-∞=AUC0-t+Ct / λZ where Ct is the last measurable concentration and λZ is the apparent terminal elimination rate constant λz apparent terminal elimination rate constant, where λZ is the magnitude of the linear regression slope of the log concentration versus time curve during the terminal phase t 1 / 2 The apparent terminal elimination half-life (whenever possible), where t 1 / 2 =(ln2) / λZ CL / F oral clearance, calculated as dose / AUC0-∞ Vd / FOral distribution volume, calculated as dose / AUC0-∞·λZ C 48 Concentrations 48 hours after administration

[0273] The pharmacokinetic parameters determined were: area under the concentration-time curve (AUC), area under the concentration-time curve from time zero to the last measurable concentration after administration (AUC 0-t ) and the area under the concentration-time curve (AUC 0-∞ ), the maximum observed concentration (C max ), reaching C max The time (t max ), concentration 48 hours after administration (C 48 ), terminal elimination half-life (t 1 / 2), oral clearance (CL / F) and apparent terminal elimination rate constant (λz).

[0274] If creatinine clearance (CL) is determined using the Cockcroft-Gault formula CR ) is less than 90mL / min (CL CR The subjects were defined as having renal impairment if the CLcr was less than 90 mL / min. The subjects were divided into groups according to the degree of renal impairment: mild (CLcr ≥ 60 and less than 90 mL / min), moderate (CL CR ≥30 and <60 mL / min), or severe (CL CR ≥15 and <30 mL / min)

[0275] The plasma and urine pharmacokinetics of migalastat have been studied in healthy volunteers and Fabry patients with normal to mildly impaired renal function. In single-dose studies, migalastat had a moderate absorption rate, with maximum concentrations reached approximately 3 hours (range, 1 to 6 hr) after oral administration over the dose range studied. Following oral doses of 75 mg to 1250 mg migalastat, mean C max and AUC 0-t The values ​​increase in a dose-proportional manner. The mean elimination half-life (t 1 / 2 ) ranged from 3.04 to 4.79 hours. The mean percentage of dose recovered in urine relative to the dose assessed 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. In the multiple ascending dose study, only minimal accumulation of plasma migalastat was observed. In the TQT study, migalastat had negative effects on cardiac repolarization at single doses of 150 mg and 1250 mg (Johnson et al., Clin Pharmacol Drug Dev. 2013 April; 2(2): 120-32).

[0276] In this single-dose renal impairment study in non-Ifabri subjects, plasma concentrations of a single dose of migalastat HCl 150 mg increased with increasing degree of renal impairment compared to subjects with normal renal function. Following a single oral dose of migalastat HCl 150 mg, mean plasma migalastat AUC in subjects with mild, moderate, or severe renal impairment was significantly increased compared to healthy control subjects. 0-∞ After a single dose, plasma migalastat AUC increased by 1.2-fold, 1.8-fold, and 4.5-fold, respectively, compared with subjects with normal renal function. 0-∞The increase in values ​​was statistically significant in subjects with moderate or severe renal impairment, but not in subjects with mild renal impairment. max Slightly delayed; after a single oral dose of migalastat HCl 150 mg, C max Compared with healthy control subjects, there was moderate (mainly from Cr CL Plasma migalastat C was lower in subjects with renal impairment (<50 mL / min) and subjects with severe renal impairment. 48 Plasma migalastat levels were elevated in subjects with normal renal function and subjects with mild, moderate, or severe renal impairment. 1 / 2 The mean CL / F increased with the increase 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] h, respectively). The mean CL / F decreased with the increase of renal failure, and the mean CL / F ranged from 12.1 to 2.7 L / hr from mild to severe renal impairment (Johnson et al., American College of Clinical Pharmacology 4.4 (2015): 256-261).

[0277] Compared with subjects with normal renal function, the clearance of migalastat decreased with increasing renal impairment, resulting in a decrease in the plasma t 1 / 2 , AUC 0-∞ and C 48 The incidence of adverse events was comparable across all renal function groups.

[0278] After a single oral dose of 150 mg migalastat HCl, plasma exposure (expressed as AUC 0-t ) increases with the degree of renal damage. Figure 1A Migalastat AUC is shown 0-t Value increases with CL CR increases as the value decreases. Figure 1B Mean (SE) plasma migalastat concentration-time curves for each renal function group are shown. BLQ values ​​were entered as zero and were included in the mean calculations.

[0279] like Figure 1C As shown, with the worsening of renal impairment, the plasma migalastat AUC 0-t The results showed that as renal damage worsens, the plasma clearance of migalastat decreases, resulting in t 1 / 2 Extension, C48 Increased values ​​and total plasma exposure (AUC 0-∞ ) were elevated, particularly in subjects with severe renal impairment. Migalastat is excreted primarily in the urine unchanged. Therefore, increases in plasma migalastat exposure were consistent with worsening renal impairment.

[0280] Conclusion: The plasma clearance of migalastat decreases with the increasing degree of renal impairment.

[0281] A summary of the PK results is shown in Table 3 below. Table 3

[0282] Example 2: Multiple-dose simulation in subjects with renal impairment

[0283] In the renal impairment study of Example 1, at eGFR values ​​≤ 35 mL / min, significant differences in the area under the curve (AUC) and trough concentrations (Cmax) of migalastat at 48 hours following QOD dosing were observed relative to subjects with normal renal function. 48 ) with a consistent increase of 2 to 4 times.

[0284] Development of a population PK model to predict exposure and IC in Fabry patients with varying degrees of renal impairment 50 This example provides a computer simulation of dosing to the renal impairment subjects of Example 1. The key assumption is that the exposure characterized in the non-Fabry renal impairment subjects with renal impairment is the same as in the Fabry patients with renal impairment. The software program is WinNonlin 5.2 or higher. The conditions of the model are described below. BSA adjusted eGFR Cockcroft-Gault ≤35mL / min / 1.73m 2 Eleven subjects were included in the modeling exercise; 3 had moderate renal impairment but ≥30 mL / min / 1.73 m 2 and ≤35mL / min / 1.73m 2 ; and 8 patients ≥14mL / min / 1.73m 2 and <30 mL / min / 1.73 m 2 The seventh dose was assumed to be steady state.

[0285] A 2-compartment model was used to estimate Vd and elimination rate constants from the single-dose data. These estimates were input into each molecule dose simulation protocol.

[0286] Figure 2 The average simulated profile for the 150 mg migalastat HCl QOD dosing regimen is shown. Table 4 below shows the exposure and accumulation rates.

[0287] Figure 3 The AUC and C from Example 1 are shown. 48 This bar graph provides the relationship between AUC and C at all levels of renal function. 48 concentrations, and demonstrated that the two values ​​are visually well correlated. Table 4 Example 3: Pharmacokinetics of migalastat in Fabry patients with renal impairment

[0288] The above computer modeling provides a scheme for plasma migalastat exposure, but cannot explain the renal impairment of Fabry patients. That is, the data does not include the pharmacodynamic component (plasma hemolysis 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 concentration of P1 compared with the study of ERT-naive Fabry patients and moderately impaired subjects from the renal impairment study of Example 1. Two groups of migalastat concentration measurements were conducted 6 months apart, and the patient had previously been treated with migalastat. Table 6 shows similar information for P2, except compared with the severely impaired patients from the renal impairment study of Example 1. The ERT-naive study was conducted in Fabry patients with compliant mutations, in which population PK was performed by sparse blood sampling. Comparison with the results of the ERT-naive study allows comparison of the PK in the Fabry population of Fabry patients who are mostly normal but have some mild and a few moderately impaired Fabry patients. No patients in the ERT-naive study had severe renal impairment, as these patients were excluded from the study. Table 5 Table 6

[0289] As can be seen from Table 5, C 48 Although the concentration increased by 49%, it was still similar to that of the Example 1 ilframbrie subject with moderate renal impairment. max This is a 33% increase, but still similar to Example 1. For moderate renal impairment, C 24 Similar to Example 1. For moderate damage, eGFR MDRD Also still within range (32mL / min).

[0290] The percentages in brackets are relatively high coefficients of variation, which correspond to changes in concentrations at time 0 h or time 48 h. This result may be due to the fact that half of the subjects with moderate renal impairment from Example 1 had low concentrations and the other half had high concentrations.

[0291] For P1 (third and fourth columns), the concentration at 48 hours is higher than the concentration at 0 hours, but for the person with moderate impairment from Example 1, the concentration at 48 hours is the same as the concentration at 0 hours. This is because blood samples were collected at time 0 and 48, respectively, in P1. However, the repeated dose modeling simulation output from the single dose data was used in Example 1, so these values ​​are the same.

[0292] A similar trend can be seen in Table 6. Thus, Tables 5 and 6 demonstrate that migalastat has similar pharmacokinetics in Fabry and Non-Fabry patients with similar renal impairment.

[0293] Figure 4 Plasma migalastat trough concentrations (C 48 ) is related to the renal impairment study of Example 1. Figure 5 The relationship of mean (SD) renal impairment study exposure to the estimated AUC for Fabry patients is shown. As can be seen from the figure, P1 and P2 follow the general trend of the renal impairment study results in non-Fabry patients.

[0294] Table 7 below shows the lyso-GB3 / eGFR of P1. Table 7

[0295] Although renal function continued to decline to an estimated GFR of 32 mL / min / 1.73 m 2 , however, plasma lysoGB3 still did not show clinically relevant changes relative to previous visits, and plasma migalastat concentrations remained similar to those observed in ilframbria patients with moderate renal impairment.

[0296] This study demonstrated that renal impairment and pharmacokinetic trends in Fabry patients correlated with those in non-Fabry patients.

[0297] Example 4: Additional simulations for subjects with renal impairment

[0298] This example provides additional computer simulations of the dosing of migalastat to the renal impairment subjects of Example 1.

[0299] Figures 6A-6D The simulated median and observed migalastat concentrations versus time for normal, severe, mild, and moderate renal impairment subjects are shown, respectively. The data are shown in Table 8 below: Table 8 a Geometric mean (CV%) c Mean (SD)

[0300] Figures 7A-7D Simulated C values ​​for subjects with normal, mild, moderate, and severe renal impairment are shown. max , AUC, C min and C 48 .

[0301] Figures 8A-8D Steady-state predictions for QOD are shown. Dashed line is the mean of the QT study. Figures 9A-9D The C of the same simulation is shown respectively. max , AUC, C min and C 48 .

[0302] Example 5: Clinical Outcomes of Miglustat Therapy in Fabry Patients with Renal Impairment and / or Elevated Proteinuria

[0303] As mentioned above, several studies have been conducted in Fabry patients using 150 mg migalastat hydrochloride every other day (QOD). One study was a 24-month trial in 67 ERT-naive patients that included a 6-month double-blind, placebo-controlled period. The other study was an active-controlled, 18-month trial in 57 ERT-experienced patients with a 12-month open-label extension period (OLE). Both the ERT-naive and ERT-experienced studies included patients with an eGFR ≥ 30 mL / min / 1.73 m 2 Fabry patients. The study design of these studies is shown in Figures 10A-10B middle.

[0304] In studies that have undergone ERT, the primary efficacy parameter was GFR (mGFR) measured using iohexol clearance. 碘海醇 ) Annualized rate of change from baseline to month 18 (mL / min / 1.73m 2 / year) and eGFR (eGFR) measured using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula CKD-EPI eGFR (eGFR) measured using Modification of Diet in Renal Disease was also calculated. MDRD )’s annual rate of change.

[0305] In the ERT-naive study, the primary efficacy parameter was GL-3 content per renal interstitial capillary. 碘海醇 , eGFR CKD-EPI and eGFR MDRD Renal function was assessed.

[0306] A post hoc analysis of data from the ERT-naive study examined patients with moderate renal impairment (30 to <60 mL / min / 1.73 m 2 ), mild renal impairment (60 to <90 mL / min / 1.73 m 2 ) and normal renal function (≥90mL / min / 1.73m 2 eGFR based on baseline eGFR in a subgroup of compliant patients CKD-EPI Annualized change in eGFR from baseline to 18 / 24 months CKD-EPI The annual rate of change is shown in Fig.11 In. Fig.11 As can be seen in the figure, patients with moderate renal impairment have a lower eGFR CKD-EPI The mean ± SEM annual change rate was -0.7 ± 3.97 mL / min / 1.73 m 2 / year, eGFR in patients with mild renal impairment CKD-EPI The average change rate was -0.8±1.01mL / min / 1.73m 2 / year, and the eGFR of patients with normal renal function CKD-EPI The average annual change rate was 0.2±0.90mL / min / 1.73m 2 This data shows that stabilization of renal function with migalastat treatment was observed regardless of baseline eGFR.

[0307] A post hoc analysis of data from studies that had undergone ERT examined patients with mild / moderate renal impairment (30 to <90 mL / min / 1.73 m 2 ) and normal renal function (≥90mL / min / 1.73m 2 ) based on the eGFR at baseline CKD-EPI and mGFR 碘海醇 Annualized change in eGFR from baseline to 18 months in patients receiving migalastat therapy (patients with a compliant mutation) and ERT CKD-EPI and mGFR 碘海醇 The annual change rates are shown in Figures 12A-12B In. Fig. 12A As can be seen in the figure, patients with normal renal function had a lower eGFR when receiving migalastat therapy. CKD-EPI The average annual change rate is -0.4mL / min / 1.73m 2 / year, and -1.03mL / min / 1.73m while receiving ERT 2 / year. eGFR in patients with mild or moderate renal impairment receiving migalastat therapy CKD-EPIThe average annual change rate is -3.33mL / min / 1.73m 2 / year, and -9.05 mL / min / 1.73 m while receiving ERT 2 / year. Fig. 12B As can be seen in the figure, patients with normal renal function had a lower mGFR 碘海醇 The average annual change rate is -4.35mL / min / 1.73m 2 / year, and -3.24 mL / min / 1.73 m while receiving ERT 2 / year. mGFR in patients with mild or moderate renal impairment receiving migalastat therapy 碘海醇 The average annual change rate is -3.51mL / min / 1.73m 2 / year, and -7.96 mL / min / 1.73 m while receiving ERT 2 This data shows that migalastat therapy and ERT have comparable beneficial effects on renal function using both GFR approaches.

[0308] Another post hoc analysis of data from studies that had undergone ERT examined patients with moderate renal impairment (30 to <60 mL / min / 1.73 m 2 ), mild renal impairment (60 to <90 mL / min / 1.73 m 2 ) and normal renal function (≥90mL / min / 1.73m 2 ) based on the eGFR at baseline CKD-EPI Annualized change rates. The annualized change rates from baseline to 18 months in patients receiving migalastat therapy (patients with a compliant mutation) and ERT are shown in Fig.13 In. Fig.13 As can be seen in the figure, patients with normal renal function had a lower eGFR when receiving migalastat therapy. CKD-EPI The mean ± SE annual change rate was -2.0 ± 0.57 mL / min / 1.73 m 2 / year, and -2.1±1.60mL / min / 1.73m while receiving ERT 2 / year. eGFR in patients with mild renal impairment receiving migalastat therapy CKD-EPI The mean ± SE annual change rate was -0.2 ± 1.25 mL / min / 1.73 m 2 / year, and -7.3±6.01mL / min / 1.73m while receiving ERT 2 / year. eGFR in patients with moderate renal impairment receiving migalastat therapy CKD-EPIThe mean ± SE annual change rate was -4.5 ± 2.68 mL / min / 1.73 m 2 / year and 1.3 mL / min / 1.73 m2 while receiving ERT 2 / year. This data shows that migalastat stabilizes renal function regardless of whether the patient has 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 some form of renal impairment.

[0309] Further analyses of the data from these studies examined eGFR based on baseline renal function. CKD-EPI The annual change rate of LVMi, WBC α-Gal A activity and plasma lysed Gb3 level. The results of each renal subgroup are shown in Table 9 below, where the ERT-naive study subgroups were based on eGFR MDRD and have undergone ERT based on mGFR 碘海醇 . Table 9

[0310] As can be seen in Table 9, in the ERT-naive study, in both renal subgroups, migalastat reduced plasma hemolytic Gb3 and LVMi at month 24, and increased WBC α-Gal A activity. In addition, regardless of renal function, in the ERT-naive study, migalastat (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) reduced renal interstitial capillary GL-3 inclusions from baseline to month 6. Table 9 also shows that in the study that had undergone ERT, in both renal subgroups, LVMi decreased, WBC α-Gal A activity increased, and hemolytic Gb3 remained low and stable during 18 months of treatment with migalastat. Table 9 also shows that in both studies that were ERT-naive and those that had undergone ERT, baseline eGFR ≥ 60 mL / min / 1.73 m 2 The renal function of the patients was stabilized. This data further supports the efficacy of migalastat when administered to patients with some forms of renal impairment.

[0311] In addition to the studies described above, other patients received migalastat therapy in other studies (e.g., dose-finding studies and / or long-term extension studies). Patients who completed some studies were eligible to continue open-label migalastat HCl 150 mg every other day in a separate extension study.

[0312] Further analysis was performed on 12 patients who completed multiple studies. Linear regression was used to calculate eGFR CKD-EPI Annual Change from Baseline. At the time of this analysis, the 12 patients had received migalastat for a mean of 8.2 (standard deviation [SD], 0.83) years, had been on treatment for a median of 8.4 (range, 6.3-9.3) years, and 11 patients had received migalastat HCl 150 mg QOD for ≥17 months. The baseline demographics of the 12 patients are shown in Table 10 below: Table 10

[0313] These patients have eGFR CKD-EPI The annual rates of change are shown in Table 11 below: Table 11 a The entire duration of migalastat treatment was included, including the period when patients received various dosing regimens of migalastat and the period when patients received migalastat HCl 150 mg every other day

[0314] As can be seen in Table 11, in these 12 patients, renal function remained stable (eGFR CKD-EPI Annual average change rate, -0.67mL / min / 1.72m 2 [95% CI -1.32, -0.02]). In an analysis of 11 patients (mean exposure, 4-5 years) who received migalastat HCl 150 mg QOD for ≥17 months, renal function also remained stable (eGFR CKD-EPI Annual average change rate, 0.24mL / min / 1.72m 2 [95% CI -1.7, 2.2]). The renal results of these 11 patients based on gender and baseline proteinuria level are shown in Table 12 below: Table 12

[0315] These results demonstrate stabilization of renal function in male and female patients with Fabry disease and a compliant mutation treated with migalastat for up to 9 years. These effects were observed over a wide range of baseline proteinuria.

[0316] Another analysis was performed on patients who participated in multiple studies using migalastat. eGFR was calculated based on proteinuria at baseline (<100, 100-1000, >1000 mg / 24h) CKD-EPI and eGFR MDRD A total of 52 ERT-naive patients with compliant 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 in these patients. Table 13

[0317] As can be seen from Table 13, most patients (67%) had proteinuria levels between 100-1000 mg / 24h at baseline; 23% of patients had baseline proteinuria levels <100 mg / 24h, and 10% had levels >1000 mg / 24h. The median treatment duration for the baseline proteinuria subgroup ranged from 3.5 to 4.8 years (maximum, 5.3 years).

[0318] These patients' eGFR according to baseline proteinuria treated with migalastat CKD-EPI The annual rates of change are shown in Table 14 below. Table 14

[0319] As can be seen in Table 14, during migalastat treatment, the eGFR of most patients with baseline proteinuria ≤1000 mg / 24 h was CKD-EPI eGFR was observed in patients with proteinuria >1000 mg / 24 h at baseline. CKD-EPI decline.

[0320] eGFR MDRD The results are consistent with the eGFR reported in the literature for untreated patients with Fabry disease. MDRD Changes were compared (natural history cohort; Schiffmann R et al. Nephrol Dial Transplant. 2009; 24:2102-11) and are shown in Table 15 below: Table 15

[0321] As shown in Table 15, across proteinuria categories, the mean annual rate of change in eGFR for patients treated with migalastat was generally less than that observed in the natural history cohort. Although the mean eGFR decreased in all untreated subgroups, patients with baseline proteinuria <100 mg / 24h (males) and 100-1000 mg / 24h (males and females) saw increases with migalastat. Regardless of treatment, patients with baseline proteinuria >1000 mg / 24h had a decrease in eGFR; however, patients treated with migalastat had less of a decrease compared to the natural history cohort. Therefore, long-term migalastat treatment is generally associated with stable renal function in patients with Fabry disease and a compliant mutation, regardless of baseline proteinuria levels.

[0322] The patents and scientific literature mentioned herein establish the 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, manuscripts and scientific literature cited herein are hereby incorporated by reference.

[0323] While the invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made without departing from the scope of the invention as encompassed by the appended claims.

Claims

1. Use of an effective amount of migalastat or a salt thereof in the preparation of a medicament for stabilizing plasma globulin (lysoGb3) in a patient diagnosed with Fabry disease and having mild renal impairment, wherein the effective amount of migalastat or a salt thereof is administered to the patient at a frequency of once every other day, wherein the effective amount is about 100 mg to about 150 mg free base equivalent (FBE), wherein administration of the migalastat or a salt thereof is effective in stabilizing the patient's plasma lysoGb3, and wherein the patient is a patient who has undergone enzyme replacement therapy (ERT), wherein a patient who has undergone ERT refers to a Fabry patient who has received ERT for at least 12 months immediately prior to starting migalastat therapy, wherein after administration of the migalastat or a salt thereof, the patient's lysoGb3 changes from baseline by 1.9 (5.8) nmol / L (SD).

2. The use according to claim 1, wherein the migalastat or its salt is in a solid dosage form.

3. The use according to claim 1, wherein the migalastat or its salt is administered orally.

4. The use according to claim 1, wherein the migalastat or a salt thereof is administered for at least 28 days.

5. The use according to claim 1, wherein the migalastat or a salt thereof is administered for at least 6 months.

6. The use of claim 1, wherein the migalastat or a salt thereof is administered for at least 12 months.

7. The use of claim 1, wherein the effective amount is about 123 mg FBE.

8. The use of claim 1, wherein the effective amount is about 123 mg of migalastat free base.

9. The use of claim 1, wherein the effective amount is about 150 mg of migalastat hydrochloride.

10. The use of claim 1, wherein the patient has a HEK assay amenable mutation in α-galactosidase A.

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