TW201907921A - Treatment of fabry disease in ert-naive and ert-experienced patients - Google Patents

Abstract

Provided are dosing regimens for the treatment of Fabry disease in a patient. Certain methods relate to the treatment of ERT-experienced or ERT-naive Fabry patients. Certain methods comprise administering to the patient about 123 mg free base equivalent of migalastat for improving left ventricular mass and/or improving podocyte globotriaosylceramide.

Description

Treatment of Fabry disease in patients with initial ERT and who have undergone ERT

The principles and embodiments of the present invention generally relate to the use of a pharmacological partner for the treatment of lysosomal storage disorders, particularly for the treatment of migalastat of Fabry disease. .

Fabry disease is a progressive X-linked defect in congenital glycosphingolipid metabolism, which is caused by the lysosomal enzyme α-galactosidase A as a result of the α-Gal A gene (GLA) mutation ( Caused by a lack of α-Gal A). Despite X-linked disorders, women may exhibit varying degrees of clinical performance. Fabry disease is a rare disease, and the incidence is estimated to be in the general population of 40,000 males to 117,000. In addition, there are late-type variants of Fabry disease that may be below the diagnostic criteria because they do not exhibit typical signs and symptoms. This situation, as well as newborn screening for Fabry disease, suggests that the actual incidence of Fabry disease may be higher than current estimates.

If left untreated, the life expectancy of Fabry patients is reduced, usually around 40 or 50 years of age due to vascular disease affecting the kidneys, heart and/or central nervous system. Enzyme deficiency leads to the accumulation of the substrate, the spherical triterpenoid guanamine (GL-3), in the cells of the systemic vascular endothelium and visceral tissues. Due to glycosphingolipid deposition, progressive decline in renal function and development of azotemia usually occur between the ages of 30 and 50, but it may occur as early as the age of twenty. Kidney damage is found in both hemizygous (male) and heterozygous (female) patients.

Heart disease caused by Fabry disease occurs in most men and many women. Early heart findings include left ventricular enlargement, heart valve involvement, and conduction abnormalities. Mitral regurgitation is the most common valvular injury typically found in children or adolescents. Cerebral vascular manifestations are mainly caused by multifocal small vessel involvement and may include thrombosis, transient ischemic attack, basilar artery ischemia and aneurysm, seizures, hemiplegia, hemiplegia, aphasia, labyrinthine disorder Or cerebral hemorrhage. The mean age of onset of cerebrovascular manifestations was 33.8 years. Personality and psychotic behavior may be manifested as they age.

The current FDA-approved treatment for Fabry disease is enzyme replacement therapy (ERT). Two alpha-GAL A products are currently available for the treatment of Fabry's disease: alpha-galactosidase (Replagal®, Shire Human Genetic Therapies) and beta-galactosidase (Fabrazyme) ®; Genzyme Corporation). These two forms of ERT are intended for intravenous administration of recombinant enzyme forms to compensate for insufficient alpha-Gal A activity in patients. Although ERT is effective in many situations, this treatment is limited. There is no evidence that ERT reduces the risk of stroke, myocardial response is slow, and GL-3 is limited in its elimination from some cell types in the kidney. Some patients also develop an immune response to ERT.

Therefore, there is still a need for a therapy for the treatment of Fabry disease.

Various aspects of the invention relate to the use of migalastat for the treatment of Fabry disease in patients with ERT-naïve and who have undergone ERT.

One aspect of the invention relates to a method of reducing a left ventricular mass index (LVMi) in a patient suffering from Fabry disease who has undergone ERT, the method comprising administering to the patient an effective amount of migalastat every other day Or a formulation of a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE).

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

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, milgasstat or a salt thereof is administered for at least 30 months.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 5 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced. In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 6.6 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 2 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced. In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 3.8 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced.

In one or more embodiments, administration of milgastastat or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 5 g/m ² of the LVH patient group that has undergone ERT. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof, provides about 9 g/m ² of LVMi in an LVH patient group that has undergone ERT. The average is reduced.

Another aspect of the invention relates to a method of reducing LVM in a patient with Fabry disease who is initially treated with ERT, the method comprising administering to the patient an effective amount of migalastat or a salt thereof every other day. The effective amount is about 123 mg of FBE.

In one or more embodiments, the patient has LVH prior to the start of administration of miggasstat or a salt thereof.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, milgasstat or a salt thereof is administered for at least 30 months.

In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 18 to 24 months, provides at least about 5 g/m ^{2 of the} group of patients with ERT initial treatment. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 18 to 24 months, provides about 7.7 g/m ² of the group of patients with ERT initial treatment. The average of LVMi is reduced.

In one or more embodiments, administration of migaster or a salt thereof provides at least about 10 g/m ^{2 of the} group of patients with initial ERT after 30 to 36 months of administration of miggasstat or a salt thereof. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides about 17 g/m ² of the group of patients with ERT initial treatment. The average of LVMi is reduced.

In one or more embodiments, administration of milgastastat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides at least about 15 g/m in the group of LVH patients who have undergone ERT The average of ² LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides about 20.8 g/m ² in the LVH patient group for ERT initial treatment. The average of LVMi is reduced.

Another aspect of the invention relates to a method of normalizing LVMi in a patient suffering from Fabry disease, the method comprising administering to the patient every other day a formulation comprising an effective amount of migaster or a salt thereof, wherein The effective amount is about 123 mg of FBE.

In one or more embodiments, the patient has LVH prior to the start of administration of miggasstat or a salt thereof.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, milgasstat or a salt thereof is administered for at least 30 months.

Another aspect of the invention relates to a method of normalizing LVMi in a patient suffering from Fabry disease who has undergone ERT, the method comprising administering to the patient an effective amount of migalastat or a salt thereof every other day. A formulation wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, the patient has LVH prior to the start of administration of miggasstat or a salt thereof.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, milgasstat or a salt thereof is administered for at least 30 months.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 5 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced. In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 6.6 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 2 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced. In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 3.8 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced.

In one or more embodiments, administration of milgastastat or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 5 g/m ² of the LVH patient group that has undergone ERT. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof, provides about 9 g/m ² of LVMi in an LVH patient group that has undergone ERT. The average is reduced.

Another aspect of the invention relates to a method of normalizing LVM in a patient with Fabry disease who is initially treated with ERT, the method comprising administering to the patient an effective amount of migalastat or a salt thereof every other day. A formulation wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, the patient has LVH prior to the start of administration of miggasstat or a salt thereof.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, migasitastat or a salt thereof is administered for at least 30 months.

In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 18 to 24 months, provides at least about 5 g/m ^{2 of the} group of patients with ERT initial treatment. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 18 to 24 months, provides about 7.7 g/m ² of the group of patients with ERT initial treatment. The average of LVMi is reduced.

In one or more embodiments, administration of migaster or a salt thereof provides at least about 10 g/m ^{2 of the} group of patients with initial ERT after 30 to 36 months of administration of miggasstat or a salt thereof. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides about 17 g/m ² of the group of patients with ERT initial treatment. The average of LVMi is reduced.

In one or more embodiments, administration of milgastastat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides at least about 15 g/m in the LVH patient group for ERT initial treatment. The average of ² LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides about 20.8 g/m ² in the LVH patient group for ERT initial treatment. The average of LVMi is reduced.

Another aspect of the invention relates to a method of reducing podocyte GL-3 in a patient suffering from Fabry disease, the method comprising administering to the patient an effective amount of migalastat or a salt thereof every other day. The effective amount is about 123 mg of FBE.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 6 months.

In one or more embodiments, the patient is an ERT initial patient.

In one or more embodiments, the patient is a patient who has undergone ERT.

Another aspect of the invention relates to a method of reducing podocyte volume in a patient suffering from Fabry disease, the method comprising administering to the patient an formulation comprising an effective amount of migalastat or a salt thereof every other day, Wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 6 months.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 30% of the podocyte volume in the group of patients with initial ERT administration. The average is reduced.

In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof, provides an average of about 47% of the podocyte volume in the group of patients with initial ERT treatment. reduce.

In one or more embodiments, the patient is an ERT initial patient.

In one or more embodiments, the patient is a patient who has undergone ERT.

Another aspect of the invention relates to a method of reducing the volume of GL-3 inclusions per foot cell in a patient suffering from Fabry disease, the method comprising administering to the patient an effective amount of MiGasi every other day A formulation of him or a salt thereof, wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 6 months.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 30% of each podocyte in the group of patients with ERT initial treatment The average volume of GL-3 inclusions is reduced.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 50% of each podocyte in the group of patients with ERT initial treatment. The average reduction in the volume of GL-3 inclusions.

In one or more embodiments, the patient is an ERT initial patient.

In one or more embodiments, the patient is a patient who has undergone ERT.

Another aspect of the invention relates to a method of treating a Fabry-Perfect patient who has undergone ERT by reducing left ventricular mass (LVM), the method comprising administering to a patient in need thereof an effective amount of MiG every other day A formulation of sitamin or a salt thereof, wherein the effective amount is about 123 mg of FBE.

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

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, milgasstat or a salt thereof is administered for at least 30 months.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 5 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced. In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 6.6 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 2 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced. In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 3.8 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced.

In one or more embodiments, administration of milgastastat or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 5 g/m ² of the LVH patient group that has undergone ERT. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof, provides about 9 g/m ² of LVMi in an LVH patient group that has undergone ERT. The average is reduced.

Another aspect of the invention relates to a method of treating a newly diagnosed EB's Fabry patient by reducing LVM, the method comprising administering to a patient in need thereof an effective amount of migalastat or a salt thereof every other day A formulation wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, the patient has LVH prior to the start of administration of miggasstat or a salt thereof.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, milgasstat or a salt thereof is administered for at least 30 months.

In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 18 to 24 months, provides at least about 5 g/m ^{2 of the} group of patients with ERT initial treatment. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 18 to 24 months, provides about 7.7 g/m ² of the group of patients with ERT initial treatment. The average of LVMi is reduced.

In one or more embodiments, administration of migaster or a salt thereof provides at least about 10 g/m ^{2 of the} group of patients with initial ERT after 30 to 36 months of administration of miggasstat or a salt thereof. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides about 17 g/m ² of the group of patients with ERT initial treatment. The average of LVMi is reduced.

In one or more embodiments, administration of milgastastat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides at least about 15 g/m in the group of LVH patients who have undergone ERT The average of ² LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides about 20.8 g/m ² in the LVH patient group for ERT initial treatment. The average of LVMi is reduced.

Another aspect of the invention relates to a method of treating a Fabry patient by normalizing LVMi, the method comprising administering to a patient in need thereof a formulation comprising an effective amount of migalastat or a salt thereof every other day Where the effective amount is about 123 mg of FBE.

In one or more embodiments, the patient has LVH prior to the start of administration of miggasstat or a salt thereof.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, milgasstat or a salt thereof is administered for at least 30 months.

Another aspect of the invention relates to a method of treating a Fabry-Perfect patient who has undergone ERT by normalizing LVMi, the method comprising administering to a patient in need thereof an effective amount of migalastat or its A formulation of a salt wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, the patient has LVH prior to the start of administration of miggasstat or a salt thereof.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, milgasstat or a salt thereof is administered for at least 30 months.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 5 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced. In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 6.6 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 2 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced. In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 3.8 g/m ² of LVMi in a patient group that has undergone ERT. The average is reduced.

In one or more embodiments, administration of milgastastat or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 5 g/m ² of the LVH patient group that has undergone ERT. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof, provides about 9 g/m ² of LVMi in an LVH patient group that has undergone ERT. The average is reduced.

Another aspect of the invention relates to a method of treating an ERT-infected Fabry patient by normalizing LVMi, the method comprising administering to a patient in need thereof an effective amount of migalastat or its A formulation of a salt wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, the patient has LVH prior to the start of administration of miggasstat or a salt thereof.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 18 months.

In one or more embodiments, migasitastat or a salt thereof is administered for at least 30 months.

In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 18 to 24 months, provides at least about 5 g/m ^{2 of the} group of patients with ERT initial treatment. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 18 to 24 months, provides about 7.7 g/m ² of the group of patients with ERT initial treatment. The average of LVMi is reduced.

In one or more embodiments, administration of migaster or a salt thereof provides at least about 10 g/m ^{2 of the} group of patients with initial ERT after 30 to 36 months of administration of miggasstat or a salt thereof. The average of LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides about 17 g/m ² of the group of patients with ERT initial treatment. The average of LVMi is reduced.

In one or more embodiments, administration of milgastastat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides at least about 15 g/m in the LVH patient group for ERT initial treatment. The average of ² LVMi is reduced. In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof for 30 to 36 months, provides about 20.8 g/m ² in the LVH patient group for ERT initial treatment. The average of LVMi is reduced.

Another aspect of the invention relates to a method of treating a Fabry-Brief patient by reducing podocyte GL-3, the method comprising administering to a patient in need thereof an effective amount of migalastat or a salt thereof every other day A formulation wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 6 months.

In one or more embodiments, the patient is an ERT initial patient.

In one or more embodiments, the patient is a patient who has undergone ERT.

Another aspect of the invention relates to a method of treating a Fabry patient by reducing the podocyte volume, the method comprising administering to a patient in need thereof an effective amount of migalastat or a salt thereof every other day. The effective amount is about 123 mg of FBE.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 6 months.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 30% of the podocyte volume in the group of patients with initial ERT administration. The average is reduced.

In one or more embodiments, administration of miggasstat or a salt thereof, after administration of miggasstat or a salt thereof, provides an average of about 47% of the podocyte volume in the group of patients with initial ERT treatment. reduce.

In one or more embodiments, the patient is an ERT initial patient.

In one or more embodiments, the patient is a patient who has undergone ERT.

Another aspect of the invention relates to a method of treating a Fabry patient by reducing the volume of GL-3 inclusions per podocyte, the method comprising administering to a patient in need thereof an effective amount each other every other day A formulation of migaster or a salt thereof, wherein the effective amount is about 123 mg of FBE.

In one or more embodiments, milgasstat or a salt thereof enhances alpha-Gal A activity.

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

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

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

In one or more embodiments, milgasstat or a salt thereof is administered for at least 6 months.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides at least about 30% of each podocyte in the group of patients with ERT initial treatment The average volume of GL-3 inclusions is reduced.

In one or more embodiments, administration of migaster or a salt thereof, after administration of miggasstat or a salt thereof, provides about 50% of each podocyte in the group of patients with ERT initial treatment. The average reduction in the volume of GL-3 inclusions.

In one or more embodiments, the patient is an ERT initial patient.

In one or more embodiments, the patient is a patient who has undergone ERT.

Before the several exemplary embodiments of the invention are described, it is understood that the invention is not limited to the details of the construction or method steps listed in the following description. The invention is capable of other embodiments and of various embodiments.

Various aspects of the invention relate to a dosing regimen for administering a pharmacological partner for the treatment of Fabry disease, such as migalastat. In one or more embodiments, the migalastat dosage regimen improves one or more cardiac parameters and/or one or more renal parameters of the patient. definition

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

The term "Fabbreviation" refers to an X-linked congenital error in the catabolism of glycosphingolipids due to the lack of lysosomal a-Gal A activity. This defect results in the substrate neurosteroid trihexosides ("GL-3", also known as Gb 3 or ceramide trihexoside) and related glycosphingolipids in the heart, kidney, skin and other tissues. Accumulation of vascular endothelial lysosomes.

The term "atypical Fabry disease" refers to a patient with a predominantly a-Gal A-deficient cardiac manifestation, ie progressive GL-3 accumulation in cardiomyocytes, resulting in a significant increase in the heart, particularly the left ventricle.

A "carrier" is a female having an X chromosome with a defective α-Gal A gene and an X chromosome with a normal gene, and the X chromosome in which one or more cell types have a normal allele is inactivated. Carriers are usually diagnosed with Fabry disease.

"Patient" means a subject diagnosed with or suspected of having a particular condition. The patient can be a human or an animal.

"Fabbrew patient" refers to an individual who has been diagnosed with or suspected of having Fabry disease and has a mutant a-Gal A as further defined below. Markers of Fabry disease can occur in male hemizygous and female carriers with the same prevalence, but women are usually less affected.

The term "initial ERT patient" means that the Fabry patient has never received ERT or has not received ERT for at least 6 months prior to the start of migalastat therapy.

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

Human α-galactosidase A (α-Gal A) refers to an enzyme encoded by a human GLA gene. The complete DNA sequence of a-Gal A including introns and exons can be obtained in GenBank Accession No. X14448.1 and shown in SEQ ID NO: 1 and Figures 1A-E. The human a-Gal A enzyme consists of 429 amino acids and is available in GenBank Accession Nos. X14448.1 and U78027.1 and is shown in SEQ ID NO: 2 and Figure 2.

The term "mutant protein" includes a protein having a mutation in a gene encoding the protein which causes the protein to fail to achieve a stable conformation under conditions normally present in the endoplasmic reticulum. Failure to achieve a stable conformation results in the degradation of a large number of enzymes rather than being transported to lysosomes. Such a mutation is sometimes referred to as a "conformational mutant." Such mutations include, but are not limited to, missense mutations and small deletions and insertions within the framework.

As used herein in one embodiment, the term "mutant a-Gal A" includes a-Gal A having a mutation in a gene encoding a-Gal A, which result in the enzyme normally present in the endoplasmic reticulum A stable conformation cannot be achieved under the conditions. Failure to achieve a stable conformation results in the degradation of a large number of enzymes rather than being transported to lysosomes.

As used herein, the term "pharmacological partner" ("PC") refers to any molecule that specifically binds to a protein and has one or more of the following effects, including small molecules, proteins, peptides, nucleic acids, carbohydrates, and the like: (i) Enhancing the formation of a stable molecular conformation of the protein; (ii) inducing transport of the protein from the endoplasmic reticulum to another cellular location, preferably the natural cellular location, ie preventing endoplasmic reticulum-related degradation of the protein; (iii) preventing Aggregation of misfolded proteins; and/or (iv) restore or enhance at least a portion of the wild-type function and/or activity of the protein. A compound specifically binds to, for example, a-Gal A, meaning 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, the term does not refer to an endogenous chaperone such as BiP, or to a non-specific agent that exhibits non-specific chaperone activity to different proteins, such as glycerol, DMSO or deuterated water, ie, a chemical chaperone. In one or more embodiments of the invention, the PC can be a reversible competitive inhibitor.

A "competitive inhibitor" of an enzyme can refer to a compound that is structurally similar to the chemical structure and molecular geometry of the enzyme substrate to bind the enzyme at about the same position as the substrate. Thus, the inhibitor competes with the substrate molecule for the same active site, thereby increasing Km. If sufficient substrate molecules are available for the substitution inhibitor, competitive inhibition is generally reversible, ie the competitive inhibitor can reversibly bind. Thus, the amount of enzyme inhibition depends on the inhibitor concentration, substrate concentration, and the relative affinity of the inhibitor and substrate for the active site.

As used herein, the term "specifically binds" refers to the interaction of a pharmacological chaperone with a protein, such as a-Gal A, particularly with the amino acid residues of the protein, which are directly Participate in contact with pharmacological partners. A pharmacological partner specifically binds to a target protein, such as a-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 partner 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., co-crystallization, NMR, etc.). The active site of α-Gal A is the substrate binding site.

"Defective alpha-Gal A activity" refers to alpha-Gal A activity in cells from a patient, with or without suspected of having Fabry or any other disease (especially blood) The activity in a normal individual is lower than the normal range.

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

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

A "responder" is an individual diagnosed or suspected of having a lysosomal storage disorder, such as Fabry disease, whose cells exhibit sufficient increased alpha-Gal A activity, and/or symptoms, respectively, in response to exposure to SPC. Improvements in mitigation or replacement marking. An improved non-limiting example of a Fabry's surrogate marker is those disclosed in Hemolysis GB3 and U.S. Patent Application Publication No. US 2010/0113517.

Non-limiting examples of improved Fabry disease surrogate markers disclosed in US 2010/0113517 include increased levels of α-Gal A or activity in cells (eg, fibroblasts) and tissues; decreased accumulation of GL-3; Plasma concentration of cystine and vascular cell adhesion molecule-1 (VCAM-1) decreased; GL-3 accumulation in cardiomyocytes and valvular fibroblasts decreased; plasma sphingosine trihexosides (hemolytic GB3) decreased; heart Hypertrophy (especially the left ventricle) is reduced, valve insufficiency and arrhythmia are alleviated; proteinuria is reduced; urine concentrations of lipids (such as CTH, lactose neural amine, neuropterin) are reduced, and glucosamine and glucosamine in urine Increased urine concentration of sphingomyelin; no stratified inclusion bodies (zebras) in glomerular epithelial cells; improved renal function; mild sweating; vascular keratin tumors; and hearing abnormalities (eg, high-frequency sensorineural hearing) Loss, progressive hearing loss, sudden deafness or tinnitus) improved. Improvements in neurological symptoms include the prevention of transient ischemic attack (TIA) or stroke; and the reduction of neuropathic pain manifested by atrial paresthesia (burning or stinging of the extremities). Another type of clinical marker that can be evaluated for Fabry disease is the prevalence of harmful cardiovascular manifestations.

As used herein, the term "normalized LVMi" refers to reducing a patient's LVMi from a higher than normal range to a normal range. The normal range for female LVMi is 43-95 g/m ² and the normal range for male LVMi is 49-115 g/m ² . Thus, normalizing female patients with LVMi reduced LVMi from >95 g/m ² to 43-95 g/m ² , and normalized male patients' LVMi decreased LVMi from > 115 g/m ² to In the range of 49-115 g/m ² .

The phrase "pharmaceutically acceptable" refers to molecular entities and compositions that are physiologically tolerable and that do not typically produce an adverse reaction when administered to a human. In some embodiments, as used herein, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in an animal. Use in vivo and more specifically in the human body. The term "carrier" as used in relation to a pharmaceutical carrier refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids such as water and oils. It is preferred to use water or an aqueous salt solution and a solution of aqueous glucose and glycerol as a carrier, particularly for injectable solutions. Suitable pharmaceutical carriers are described in E. W. Martin, "Remington's Pharmaceutical Sciences", 18th edition or other edition.

The term "enzyme replacement therapy" or "ERT" refers to the introduction of a non-natural, purified enzyme into an individual having such an enzyme deficiency. The protein administered can be obtained from natural sources or by recombinant performance (as described in more detail below). The term also refers to the introduction of a purified enzyme into an individual that otherwise would require or benefit from the administration of a purified enzyme, eg, the individual suffers from an enzyme deficiency. The introduced enzyme may be a purified recombinant enzyme produced in vitro, or a protein purified from ex vivo tissues or body fluids (for example, like placenta or animal milk) or from plants.

As used herein, the term "isolated" means to remove a reference material from the environment in which it is normally found. Thus, the isolated biological material may be free of cellular components, ie, components of cells from which the material is found or produced. In the case of a nucleic acid molecule, the isolated nucleic acid includes a PCR product, an mRNA band on a gel, cDNA or a restriction fragment. In another embodiment, the isolated nucleic acid is preferably excised from a chromosome from which it can be found, and more preferably is no longer linked to a non-regulatory non-coding region, or is located when found in a chromosome. It is linked by other genes upstream or downstream of the gene contained in the isolated nucleic acid molecule. In yet another embodiment, the isolated nucleic acid lacks one or more introns. Isolated nucleic acids include sequences inserted into plasmids, cosmids, artificial chromosomes, and the like. Thus, in a specific embodiment, the recombinant nucleic acid is an isolated nucleic acid. The isolated protein may bind to other proteins or nucleic acids or both that bind to it in the cell, or to the cell membrane if its mesangium binds to the protein. The isolated organelle, cell or tissue is removed from the anatomy it finds in the organism. The separated material can be, but need not be, purified.

The terms "about" and "about" generally mean the degree of acceptable error of the amount measured given the nature or precision of the measurement. A typical exemplary degree of error is within 20% of a given value or range of values, preferably within 10%, and more preferably within 5%. Alternatively, particularly in biological systems, the terms "about" and "approximately" may mean within an order of magnitude of a given value, preferably within 10 or 5 times, more preferably at 2 times. The value inside. Numerical quantities given herein are approximate unless otherwise indicated, meaning that the term "about" or "about" can be inferred when not explicitly stated. Fabry disease

Fabry disease is a rare, progressive, and destructive X-linked lysosomal storage disorder. Mutation of the GLA gene results in a defect in the lysosomal enzyme α-Gal A (required for glycosphingolipid metabolism). From the early stages of life, a decrease in α-Gal A activity leads to accumulation of glycosphingolipids (including GL-3 and plasma hemolysis GB3) and leads to Fabry disease symptoms and life-limiting sequelae, including pain, gastrointestinal tract Symptoms, kidney failure, cardiomyopathy, cerebrovascular events, and early death. Early onset therapy and lifelong treatment offer opportunities to slow disease progression and prolong life expectancy.

Fabry's disease covers a wide range of disease severity and age at onset, although it has traditionally been divided into two major phenotypes, "classic" and "late". Classical phenotypes have largely been attributed to men with an earlier onset of undetectable to low alpha-Gal A activity and clinical manifestations of kidney, heart and/or cerebrovascular. Delayed phenotypes have primarily been attributed to men with higher residual alpha-Gal A activity and later onset of these disease manifestations. Hybrid female carriers typically exhibit a delayed phenotype, but depending on the pattern of X chromosome inactivation, a classical phenotype can also be displayed.

More than 800 GLA mutations that cause Fabry disease have been identified. Approximately 60% are missense mutations resulting in a single amino acid substitution in the alpha-Gal A enzyme. Mismatched GLA mutations typically result in the production of abnormally folded and unstable forms of a-Gal A, and most are associated with classical phenotypes. Normal cell quality control mechanisms in the endoplasmic reticulum block the transport of these abnormal proteins to lysosomes and target these abnormal proteins as premature degradation and elimination. Many missense mutant forms are targets for milagistatin (alpha-Gal A specific pharmacological partner).

The clinical manifestations of Fabry disease have a wide range of severity and are roughly related to the patient's residual alpha-Gal A levels. Most currently treated patients are referred to as classic Fabry patients, most of whom are male. These patients experience diseases of various organs, including the kidneys, heart, and brain, where the symptoms of the disease first appear in adolescence, and typically the condition continues to worsen until the fourth or fifth decade of life dies. Many recent studies have shown that a large number of undiagnosed men and women have a range of Fabry disease symptoms, such as impaired heart or kidney function and stroke, usually first in adulthood. Individuals with this type of Fabry disease, known as delayed-type Fabry disease, tend to have higher residual α-Gal A levels than classic Fabry patients. Individuals with delayed-type Fabry disease typically experience disease symptoms during adulthood, and disease symptoms typically focus on a single organ, such as enlargement of the left ventricle or progressive renal failure. In addition, delayed-type Fabry disease may also occur in the form of a stroke of unknown cause.

Fabry patients have progressive kidney damage, and untreated patients show end stage renal damage until the fifth decade of life. Defects in alpha-Gal A activity result in the accumulation of GL-3 and related glycosphingolipids in many cell types, including kidney cells. GL-3 accumulates in podocytes, epithelial cells, and tubular cells of the distal tubules and Henry's rings. Renal impairment can be manifested by decreased proteinuria and glomerular filtration rate.

Because Fabry's disease is rare and involves multiple organs, the age of onset is wide and heterogeneous, and correct diagnosis is a challenge. Health care professionals have lower awareness and frequent misdiagnosis. Once the patient has symptoms, plus mutation analysis, the diagnosis of Fabry disease is most often confirmed based on decreased alpha-Gal A activity in plasma or peripheral white blood cells (WBC). In women, the diagnosis is even more challenging because the enzymatic identification of the female carrier is less reliable due to random X chromosome inactivation in some of the carriers' cells. For example, some affirmative carriers (the daughters of males affected by orthodox) have alpha-Gal A enzyme activity ranging from normal to very low activity. Since the carrier has normal alpha-Gal A enzymatic activity in leukocytes, identification of the a-Gal A mutation by genetic testing provides accurate carrier identification and/or diagnosis.

The mutant form of α-Gal A is considered to be compliant with migalastat, when the mutant form of α-Gal A is expressed in HEK-293 cells (referred to as “HEK assay”), according to Good Laboratory Practice (Good Laboratory) Practice, GLP) Validated in vitro assay (GLP HEK or Migalastat Amenability Assay), defined as showing a relative increase of ≥ 1.20 fold (± 10 μM migalastat) and ≥ 3.0% wild Absolute increase in type (WT) (± 10 μM migalastat). These mutations are also referred to herein as "HEK assay compliance" mutations.

Previous screening methods have been provided that assess enzyme enhancement prior to initiation of treatment. For example, assays using HEK-293 cells have been used in clinical trials to predict whether a given mutation will be treated in response to a pharmacological partner (eg, migalastat). In this assay, a cDNA construct was established. The corresponding α-Gal A mutant form transiently expressed in HEK-293 cells. The cells were then incubated with migalastat (17 nM to 1 mM) for 4 to 5 days. Thereafter, the synthetic fluorescent substrate (4-MU-α-Gal) was used in the cell lysate or the α-Gal A level was measured by Western blotting. This has been done against known missenses that cause disease or small in-frame insertion/deletion mutations. Mutations previously identified in response to PC (e.g., migalastat) using such methods are listed in U.S. Patent No. 8,592,362. Pharmacological partner

Binding of a small molecule inhibitor of an enzyme associated with LSD can increase the stability of the mutant enzyme and the corresponding wild-type enzyme (see U.S. Patent Nos. 6,274,597; 6,583,158; 6,589,964; 6,599,919; 6,916,829; and 7,141,582, all incorporated herein by reference herein ). In particular, the administration of a small molecule derivative of glucose and galactose, which is a specific, selective competitive inhibitor for several target lysosomal enzymes, effectively increases the stability of the enzyme in cells in vitro, and This increases the transport of enzymes to lysosomes. Therefore, by increasing the amount of enzyme in the lysosome, the hydrolysis of the enzyme substrate is expected to increase. The original theory behind this strategy is as follows: The mutant enzyme protein is unstable in the endoplasmic reticulum (Ishii et al., Biochem. Biophys. Res. Comm. 1996; 220: 812-815) Therefore, the enzyme protein is delayed and prematurely degraded in the normal transport pathway (endoplasmic reticulum → high matrix → endosomal → lysosome). Thus, a compound that binds to and increases the stability of a mutant enzyme can act as a "companion" to the enzyme and increase the amount that can leave the endoplasmic reticulum and move to the lysosome. In addition, since some wild-type proteins are incompletely folded and transported, in some cases up to 70% of some wild-type proteins are degraded before reaching their final cellular location, so these partners can be used to stabilize wild-type enzymes, And increase the amount of enzyme that can leave the endoplasmic reticulum and be transported to the lysosome.

In one or more embodiments, the pharmacological partner comprises milgasstat or a salt thereof. As used herein, "milgastat" refers to (2R,3S,4R,5S)-2-(hydroxymethyl)acridine-3,4,5-triol, and is also known as 1-deoxygenated galactose deoxynojirimycin (1-deoxygalactonojirimycin), and is known under the trade name Galafold ^TM. In another embodiment, the pharmacological partner comprises the hydrochloride salt of migalastat. Migastat has the following structure:

As used herein, the term "free base equivalent" or "FBE" refers to the amount of migalastat present in milgasstat or a salt thereof. In other words, the term "FBE" refers to an amount of migalastat free base or an equivalent amount of migalastat free base provided by the salt of migalastat. For example, due to the weight of chloride ions, 150 mg of migalastat hydrochloride provides only as much migalastat as that provided by methicystat in the form of 123 mg of the free base. Other salts have different conversion factors depending on the molecular weight of the counterion.

Migastat is a low molecular weight imino sugar and is an analog of GL-3 terminal galactose. In vitro and in vivo pharmacological studies have demonstrated that milaginostat acts as a pharmacological partner, selectively and reversibly binding to the specific mutant forms of wild-type (WT) α-Gal A and α-Gal A with high affinity. At the locus, the genotype of this particular mutant form is referred to as HEK to determine a compliant mutation. The migabastatin combination stabilizes the mutant form of α-Gal A in the endoplasmic reticulum, facilitating its proper transfer to lysosomes, where dissociation of migalastat allows α- Gal A reduces the levels of GL-3 and other substrates. Approximately 30%-50% of patients with Fabry disease have HEK-determined compliant mutations; most of them are associated with the classical phenotype of the disease. The list of HEK assays for compliance mutations includes at least those mutations listed in Table 1 below. In one or more embodiments, if a double mutation is present on the same chromosome (male and female), if the double mutation is present in one of the entries in Table 1 (eg, D55V/Q57L), the patient is considered to be HEK measures compliance. In some embodiments, if a double mutation is present on a different chromosome (in women only), then if any of the individual mutations are present in Table 1, the patient is considered to be compliant with the HEK assay. Table 1 : Compliance mutations Administration, formulation and administration

In one or more embodiments, migalastat or a salt thereof is administered to a Fabry patient at a frequency once every other day (also referred to as "QOD"). In various embodiments, the dosages described herein relate to migalastat hydrochloride or an equivalent dose of milgasstat or a salt thereof that is not the hydrochloride salt. In some embodiments, the equal dose relates to the free base of migalastat. In an alternative embodiment, the equal dose relates to a salt of migalastat. In another embodiment, the salt of migalastat is migalastat hydrochloride. The administration of the salt of miglastatin or migalastat is referred to herein as "migastatin therapy."

It should be noted that 150 mg of migalastat hydrochloride corresponds to 123 mg of the free base form of migalastat. Thus, in one or more embodiments, the dosage is 150 mg of migalastat hydrochloride or an equivalent dose of migalastat or a salt thereof that is not hydrochloride, administered once every other day. . As mentioned above, this dose is referred to as 123 mg FBA of migalastat. In another embodiment, the dosage is 150 mg of migalastat hydrochloride every other day. In other embodiments, the dose is 123 mg of migalastat free base administered at a frequency once every other day.

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

Migastat's administration can last for a certain period of time. In one or more embodiments, the 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, 24, 30 or 36 months, or at least 1, 2, 3, 4 or 5 years. In various embodiments, the migalastat therapy is a long-term migalastat therapy for at least 6 months, such as 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.

The administration of migalastat according to the present invention may be in the form of a formulation suitable for any route of administration, but is preferably administered in an oral dosage form such as a tablet, capsule or solution. As an example, the patient is orally administered a capsule, each capsule containing 150 mg of migalastat hydrochloride or an equivalent dose of milgasstat or a salt thereof that is not hydrochloride.

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

In one embodiment of the invention, a PC (eg, milgasstat or a salt thereof) is administered as a monotherapy, and may be in a form suitable for any route of administration, including, for example, in the form of a tablet or capsule or liquid. In the form of a sterile aqueous solution for injection, or as a dry lyophilized powder (added to the formulation of the replacement enzyme during or immediately after reconstitution to prevent enzymatic aggregation in vitro prior to administration).

When a PC (for example, milgasstat or a salt thereof) is formulated for oral administration, a pharmaceutically acceptable excipient such as a binding agent (for example, pregelatinized corn starch, polyvinylpyrrolidine) can be used by a conventional means. Ketone or hydroxypropyl methylcellulose); a filler (for example, lactose, microcrystalline cellulose or calcium hydrogen phosphate); a lubricant (for example, magnesium stearate, talc or cerium oxide); a disintegrating agent (for example, These tablets or capsules are prepared by potato starch or sodium starch glycolate) or a wetting agent (for example, sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product (combined with water or other suitable vehicle before use). Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (for example, lecithin or gum arabic) a non-aqueous carrier (for example, almond oil, oil ester, ethanol or fractionated vegetable oil); or a preservative (for example, methyl or propylparaben or sorbic acid). The formulation may also contain buffer salts, flavoring, coloring, and sweetening agents, as appropriate. Formulations for oral administration may be suitably formulated to administer controlled release of the active chaperone compound.

Pharmaceutical formulations suitable for parenteral/injectable use of PC (for example, migaster or a salt thereof) generally include sterile aqueous solutions (in the case of water solubility), or dispersions and for the temporary preparation of sterile injectable solutions or dispersions Sterile powder of body. In all cases, the form must be sterile and must have fluidity to the extent that easy to inject. It must be stable under the conditions of manufacture and storage and must be resistant to microorganisms (such as bacteria and fungi). The carrier may be a solvent or dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerin, propylene glycol, polyethylene glycol, and the like), a suitable mixture thereof, and a vegetable oil. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. Different antibacterial and antifungal agents can be used. (for example, parabens, trichlorobutanol, phenol, benzyl alcohol, sorbic acid, etc.) bring the action of microorganisms In many cases, it will be reasonable to include isotonic agents, such as sugars or sodium chloride. Injectable compositions can be brought about by the use of compositions which delay the absorption of agents, such as aluminum monostearate and gelatin. Extended absorption.

If necessary, the purified enzyme (if any) and the PC (milgastat or its salt) may be incorporated in a suitable amount in a suitable solvent having the other ingredients listed above, followed by filtration or Final sterilization to prepare a sterile injectable solution. In general, dispersions are prepared by incorporating the different sterilized active ingredients into a sterile vehicle comprising the base dispersion medium and the additional ingredients required from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques which produce the active ingredient plus any additional desired ingredient powder from the prior sterile filtration solution. .

The formulation may comprise an excipient. A pharmaceutically acceptable excipient-based buffer, such as a citrate buffer, a phosphate buffer, an acetate buffer, and a bicarbonate buffer, an amino acid, urea, an alcohol, may be included in the formulation. Ascorbic acid, 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; And polyethylene glycol (eg, PEG-4000, PEG-6000); glycerin; glycine or other amino acids; and lipids. Buffer systems for use with the formulations include citrate; acetate; bicarbonate; and phosphate buffer. Phosphate buffers are preferred embodiments.

The partner compound can be administered orally or parenterally, including intravenous, subcutaneous, intraarterial, intraperitoneal, intraocular, intramuscular, buccal, rectal, vaginal, intraocular, intracerebral, intradermal, intracranial Internal, intraspinal, intraventricular, intrathecal, intracisternal, intracapsular, intrapulmonary, intranasal, transmucosal, transdermal, or via inhalation.

Administration of the above parenteral formulation of the chaperone compound can be by bolus injection of a periodic injection formulation, or can be administered from a reservoir by intravenous or intraperitoneal administration, which reservoir can be external (eg, Intravenous bag) or internal (eg bioerodible implant).

Embodiments involving pharmaceutical formulations and administration can be combined with any other embodiment of the invention, such as a method involving treating a Bray's disease patient, enhancing alpha in a patient diagnosed with or suspected of having Fabry disease -Gal A method, pharmacological partner of a-Gal A for the manufacture of a medicament for the treatment of a patient diagnosed with Fabry disease or for the treatment of a patient diagnosed with Fabry disease An embodiment of a pharmacological partner of a-Gal A, along with an embodiment involving a compliant mutation, PC, and a suitable dose thereof.

In one or more embodiments, a PC (eg, milgasstat or a salt thereof) is administered in combination with an ERT. ERT increases the amount of protein by exogenously introducing wild-type or biologically functional enzymes by infusion. This therapy has been developed for many genetic diseases, including lysosomal storage disorders (such as Fabry disease) as cited above. After infusion, the exogenous enzyme is expected to be absorbed by the tissue by a non-specific or receptor-specific mechanism. In general, the absorption efficiency is not high, and the circulation time of the foreign protein is short. Furthermore, the foreign protein is unstable and undergoes rapid intracellular degradation, along with the potential for an adverse immune response in the case of subsequent treatment. In one or more embodiments, the partner is administered concurrently with a replacement enzyme (eg, in place of a-Gal A). In some embodiments, the chaperone is co-formulated with a replacement enzyme (eg, in place of a-Gal A).

In one or more embodiments, the patient is switched from ERT to migalastat therapy. In some embodiments, a patient receiving an ERT is identified, the patient's ERT is interrupted, and the patient begins receiving migalastat therapy. The migalastat therapy can be carried out according to any of the methods described herein. Left ventricular mass index

The dosing regimen described herein can improve LVMi in Fabry patients. The natural history of LVMi and cardiac hypertrophy in untreated Fabry patients, regardless of phenotype (Patel, O'Mahony et al., 2015), showed LVMi at +4.07 and +8.0 g/m ² /year The rate between them is gradually increasing (Kampmann, Linhart et al., 2008; Wyatt, Henley et al., 2012; Germain, Weidemann et al., 2013). Since untreated Fabry patients typically exhibit an increase in LVMi over time, both the reduction and maintenance of LVMi indicate the benefit of migalastat therapy. As described in further detail in the Examples below, Phase 3 studies have found that migalastat therapy reduces LVMi in patients who have undergone ERT and ERT initial treatment, and shows even greater in LVH patients at baseline. LVMi is lowered. These Phase 3 studies also found that in some patients with LVH, migalastat therapy normalizes LVMi.

The third phase of the migalastat therapy evaluated LVMi, which is considered to be a more accurate measurement than LVM. In addition, in the third phase of the study, the ultrasound cardiogram was performed locally, but the ultrasound cardiogram was read centrally by the same reader. Using the same reader to centrally read the ultrasonic echocardiogram improves accuracy compared to partial reading of the ultrasonic echocardiogram.

Compared with the same patient who was not treated with migalastat therapy, migalastat therapy reduced the increase in LVMi in Fabry patients. In one or more embodiments, the migalastat therapy provides a change to the patient's LIVi that is less than (ie, more negative) 0 g/m ² , such as 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 . Alternatively, in one or more embodiments, migalastat therapy provides a reduction in LVMi of greater than 0 g/m ² , such as at least about 0.5, 1, 1.5, ² , 2.5, ³ , 3.5, 4.5 , 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 g/m ² reduction.

In one or more embodiments, after 18 months of administration of miggasstat or a salt thereof, migalastat therapy provides an average of LVMi of at least about 1 g/m ² in a patient group that has undergone ERT. reduce. In various embodiments, the average reduction in the group of patients who have experienced ERT after at least 18 months of administration of miggasstat or a salt thereof is at least about 1, ² , 3, 4, 5, or 6 g/m ² , for example, About 6.6 g/m ² .

In one or more embodiments, after 18 months of administration of miggasstat or a salt thereof, migalastat therapy provides an average of LVMi of at least about 1 g/m ² in a patient group that has undergone ERT. reduce. In various embodiments, the average reduction in the group of patients who have experienced ERT after administration of miggasstat or a salt thereof for at least about 1, 2, 3, 4, 5, 6, 7, or 8 g/ m ² , for example about 8.4 g/m ² .

In one or more embodiments, after 30 months of administration of miggasstat or a salt thereof, migalastat therapy provides an average of LVMi of at least about 0.5 g/m ² in a patient group that has undergone ERT. reduce. In various embodiments, the average reduction in the group of patients who have experienced ERT after administration of miggasstat or a salt thereof for at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4 g/ m ² , for example about 3.8 g/m ² .

In one or more embodiments, after 30 months of administration of miggasstat or a salt thereof, migalastat therapy provides at least about 1 g/m ² of LVMi in the LVH patient group that has undergone ERT. The average is reduced. In various embodiments, the average reduction in the LVH patient group that has undergone ERT after administration of miggasstat or a salt thereof for at least about 1, 2, 3, 4, 5, 6, 7, 8 or 9 g/m ² , for example about 9 g/m ² .

In one or more embodiments, the migalastat therapy provides at least about 1 g/m ² of LVMi in the group of patients with initial ERT after 18 to 24 months of administration of miggasstat or a salt thereof. The average is reduced. In various embodiments, the average reduction in the group of ERT-initiated patients is at least about 1, 2, 3, 4, 5, 6, or 7 g/ after 18 to 24 months of administration of miggasstat or a salt thereof. m ² , for example about 7.7 g/m ² .

In one or more embodiments, the migalastat therapy provides at least about 1 g/m ² in the ERT-initiated LVH patient group after 18 to 24 months of administration of miggasstat or a salt thereof. The average of LVMi is reduced. In various embodiments, the average reduction in the ERT-initiated LVH patient group is at least about 1, 2, 3, 4, 5, 6, 7, after 18 to 24 months of administration of miggasstat or a salt thereof. 8, ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , 14, 15, 16, 17, or 18 g/m ² , for example about 18.6 g/m ² .

In one or more embodiments, the migalastat therapy provides at least about 1 g/m ² of LVMi in the group of patients with initial ERT after 30 to 36 months of administration of miggasstat or a salt thereof. The average is reduced. In various embodiments, the average reduction in the group of ERT-initiated patients is at least about 1, 2, 3, 4, 5, 6, 7, 8 after administration of miggasstat or a salt thereof for 30 to 36 months. 9, 10, 11, 12, 13, 14, 15, 16 or 17 g/m ² , for example about 17 g/m ² .

In one or more embodiments, the migalastat therapy provides at least about 1 g/m ² in the ERT-initiated LVH patient group after 30 to 36 months of administration of miggasstat or a salt thereof. The average of LVMi is reduced. In various embodiments, the average reduction in the ERT-initiated LVH patient group is at least about 1, 2, 3, 4, 5, 6, 7, after 30 to 36 months of administration of miggasstat or a salt thereof. 8, ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , 14, 15, ¹⁶ , ¹⁷ , 18, ¹⁹ or 20 g/m ² , for example about 20.8 g/m ² . Podocyte GL-3 and podocyte volume

The dosing regimen described herein can improve one or more parameters associated with podocytes in a Fabry patient. Fabry patients typically accumulate GL-3 in podocytes. As described in further detail in the Examples below, Phase 3 studies found that migalastat therapy reduced mean podocyte volume and reduced mean podocyte GL-3 content volume.

According to two methods, the third phase of migalastat therapy evaluated podocyte GL-3. In the first method, a qualitative comparison of podocyte GL-3 was performed because there was no reliable quantitative method at the time of this study. Pathologists evaluated side-by-side digital images of baseline and post-baseline biopsies (double-blind for treatment assignment and visit date) and classified the biopsy as having more, less, or equal GL-3 in the podocytes. It is worth noting that if more or less GL-3 scores are assigned, this indicates a significant change in GL-3 between baseline and post-baseline. The three pathologists blindly determined whether the paired biopsy had an "equal" number of GL-3 inclusions in each cell type, or whether one of the pair had "less" or "one" More" inclusions. If there are 2 pathologists agreeing to "less" or "more", the agreed value is assigned, otherwise the "equal" designation is retained. The results are summarized as the percentage of samples with increased, decreased or no change in GL-3 content relative to baseline.

In the second method, post-mortem analysis is performed using stereological principles to estimate structural parameters, including mean podocyte volume, volume fraction of GL-3 inclusions in podocytes, and GL-3 inclusion in each podocyte. The total volume of the object. These stereological principles based on random geometry and statistics are designed to be unbiased, efficient, and reproducible. Electron microscopy images (about 30,000 x) were obtained from glomeruli according to a systematic, unbiased, uniform random sampling method to estimate the volume fraction (Vv) of GL-3 inclusions in podocytes [Vv(Inc/PC) )]. A grid with the appropriate dot density is superimposed on the image. These parameters are calculated by dividing the number of grid points hitting the GL-3 inclusion by the number of grid points hitting the cytoplasm of the glomerular podocytes.

In one or more embodiments, migalastat therapy can reduce podocyte volume in a Fabry patient compared to the same patient who is not receiving migalastat therapy. In one or more embodiments, the migalastat therapy reduces the podocyte volume by at least about 10%, such as at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%. %.

In one or more embodiments, the migalastat therapy provides an average reduction in podocyte volume of at least about 10% of the ERT-initiated patient group after administration of miggasstat or a salt thereof for 6 months. In various embodiments, the average reduction in the group of ERT-initiated patients after administration of miggasstat or a salt thereof is at least about 10%, 15%, 20%, 25%, 30%, 35%. 40%, 45% or 50%, for example about 47%.

In one or more embodiments, migalastat therapy can reduce the total GL-3 inclusion volume per foot cell of a Fabry patient compared to the same patient not treated with migalastat therapy . In one or more embodiments, the migalastat therapy reduces the podocyte GL-3 content by at least about 10%, such as at least about 15%, 20%, 25%, 30%, 35%, 40 %, 45% or 50%.

In one or more embodiments, after 6 months of administration of miggasstat or a salt thereof, migalastat therapy provides at least about 10% of the total GL of each podocyte in the group of patients with ERT initial treatment. 3 The average reduction in the volume of the inclusions. In various embodiments, the average reduction in the group of ERT-initiated patients after administration of miggasstat or a salt thereof is at least about 10%, 15%, 20%, 25%, 30%, 35%. 40%, 45% or 50%, such as about 50%. EXAMPLES Example 1: using a dosing regimen he hydrochloride method of treating a patient cloth Wright ERT untreated migalastat

This example describes a phase 3 study of migalastat therapy in Fabry patients with initial ERT.

The patient was selected. Eligible patients were 16-74 years old and had genetically proven Fabry disease; never received ERT or did not receive ERT ≥ 6 months; based on human embryonic kidney-293 (HEK) used at the time of enrollment assay, the response is generated having mutations GLA migalastat mutant protein; having eGFR> 30 ml / min / 1.73 m 2, and has a urinary GL-3 ≥ 4 times the upper limit of normal.

Research design. After the eligibility-baseline assessment (2 months), patients were randomized to stage 1 - double-blind administration of 150 mg of migalastat hydrochloride or placebo every other day for 6 months. All patients who completed Phase 1 are eligible to receive non-blind migasta in Phase 2 (June-December) and another year (13-April) (FACETS Study; AT1001-011/NCT00925301) ). The primary objective was to compare the effect of migalastat on renal GL-3 relative to placebo after 6 months of treatment, as assessed by histological scores of the number of inclusions in interstitial capillaries. The secondary objective of Stage 1 was to compare the effects of migalastat on urinary GL-3 levels, renal function, 24-hour urine protein, and safety and tolerability relative to placebo. The third objective is cardiac function, patient reported results, exploratory kidney analysis, and leukocyte alpha-Gal A activity. Study completions are eligible to participate in the non-blind extension study (OLE; AT1001-041/NCT01458119) for up to 5 years.

Renal histology assessment. A baseline renal biopsy was performed for each patient, along with a repeat kidney test at 6 and 12 months. The number of GL-3 inclusions per renal interstitial capillaries at baseline and at 6 and 12 months per patient was determined by 3 independent pathologists (double blind to treatment and visit) Quantitative assessment was performed in 300 capillaries. Prior to statistical analysis, all values for each individual biopsy were averaged over a given period of time.

Changes in GL-3 in podocytes, endothelial cells, and mesangial cells, as well as glomerular sclerosis, were quantitatively assessed by the same three pathologists (double blind to treatment/visit).

Neural guanamine trihexosides and sphingosine tripoly hexosides. Plasma hemolysis GB3 and 24-hour urine GL-3 were analyzed by liquid chromatography-mass spectrometry using a novel stable isotope-labeled internal standard 13C6-hemolytic GB3 (lower limit quantitation: 0.200 ng/mL, 0.254 nmol/L).

Renal function assessment. The annual rate of change (mL/min/1.73 m ² /year) was calculated using Chronic Kidney Disease Epidemiology Collaboration - eGFR _CKD-EPI and measured iohexol clearance - mGFR _iohexol of.

Ultrasound cardiography. Parameters such as LVMi, left posterior wall thickness, diastolic blood pressure, interventricular septum thickness, and diastolic blood pressure were evaluated by blind, focused evaluation. A baseline visit to the extension study AT1001-041/NCT01458119 was used as the last assessment.

The results reported by the patient. Use Gastrointestinal-Symptoms-Rating-Scale (GSRS), Short Form-36v2TM, and Brief-Pain-Inventory-Pain-Severity-Component Assess the results reported by the patient.

Safety analysis and adverse events. Randomized patients who received a dose of ≥ 1 were included in the safety analysis, which included vital signs, physical examination, electrocardiogram, clinical laboratory, and adverse events.

Statistical analysis of renal interstitial capillaries GL-3 substrate. The primary phase 1 (6 months) end point (ITT population with baseline biopsy, n = 64) decreased GL-3 content in each interstitial capillaries in the miggasstat and placebo groups ≥ The proportion of 50% of patients. Evaluation of the other two first-stage end points (modified ITT population: randomized patients with paired baseline and 6-month biopsy; n = 60): percentage of GL-3 inclusions per interstitial capillaries Changes, as well as the percentage of interstitial capillaries that do not contain GL-3 inclusions.

Efficacy analysis of GL-3 inclusions and other pre-specified endpoints for each of the interstitial capillaries in Phase 2 (September-December) and non-blind Extension (Days 12-24) is based on The following modified treatment intent (mITT): Treatment consisted of a randomized patient with a mutant alpha-Gal A enzyme that was shown to be suitable for treatment with migalastat by a validation assay; n = 50. result

Baseline characteristics. A randomized group of 67 potentially responsive mutants of a-Gal A (16-74 years old, 64% female) (ITT population). Table 2 provides baseline characteristics of 50 patients in the ITT population with the appropriate mutant a-Gal A. There were no statistically significant differences in baseline parameters. Table 2 : Baseline characteristics

Published reports of one or more clinical phenotypes associated with genotypes of patients with suitable mutations (n = 50) indicate that 30 (60%) have mutations associated with the classic Fabry disease phenotype, one ( 2%) had mutations associated with non-classical phenotypes, three (6%) had mutations associated with both phenotypes, and 16 (32%) had not been classified. Residual WBC α-Gal A activity was found to be < 3% in 14 of 16 males (87%); 29 (94%) of 31 males and females had elevated plasma hemolysis GB3, and 50 males and females Of these, 47 (94%) had multiple organ system diseases.

Migaseta and renal interstitial capillaries GL-3. In the 6-month primary outcome analysis (ITT), 13 of the 32 patients treated with migalastat (41%) and 9 of the 32 patients treated with placebo (28%) achieved a response ( The GL-3 content of each interstitial capillaries was reduced by ≥ 50%) (p = 0.30). The median number of interstitial capillaries GL-3 in the migalastat group was -40.8% from baseline, compared with -5.59% in the placebo group (p = 0.097). The mean difference in % change in interstitial capillaries without GL-3 inclusions was 7.3%, favoring migalastat (p = 0.042).

In the first phase (6 months after the event) and the second phase (pre-designated 12 months) analysis (mITT suitable population; n = 45), 6 months of migalastat compared with placebo Significantly greater reduction in the interstitial capillaries GL-3 (± SEM): -0.250 ± 0.103 vs + 0.071 ± 0.126; p = 0.008. After the other 6 months of treatment, the reduction in interstitial capillaries GL-3 remained stable at 6 months. In patients who switched from placebo to migalastat in the 6th month, a significant decrease in interstitial capillaries GL-3 (± SEM) was observed at 12 months (-0.330 ± 0.152; p = 0.014). A patient with a mutant a-Gal A that showed no suitable methalastat therapy according to the validation assay did not show any therapeutic effect in the interstitial capillaries GL-3.

Migaseta and GL-3 in glomerular cells. Based on a qualitative assessment of 23 renal biopsies, 12 months of migalastat, patients with responsive mutant α-Gal A showed glomerular podocytes (5 of 23 biopsies; 22%) Endothelial cells (6 of 23 biopsy; 26%) and renal cell GL-3 (11 of 23 biopsy; 48%). No increase in GL-3 was shown in these samples; the remaining samples did not change.

Migastastat and plasma hemolysis GB3 levels. Six months of migalastat (mITT-adapted) was associated with a significant decrease in plasma hemolysis GB3 levels compared with placebo (p = .0033). After another 6 months of miigalastat, plasma hemolysis GB3 remained stable with no further reduction. Plasma hemolysis GB3 was found to be significantly reduced (p < 0.0001) in patients who switched from placebo to miigalastat between 6 and 12 months (suitable for ITT). Plasma levels were unchanged in patients with unsuitable mutant α-Gal A.

Migastastat and urinary GL-3 substrate. In patients with the appropriate mutant α-Gal A, the mean change in 24-hour urinary GL-3 substrate (± SEM) concentration for migalastat and placebo (baseline to month 6) was: -361 ± 169 (to 555 ± 151) and -147 ± 217 (to 1017 ± 218) ng/mg creatinine (p = 0.44).

Migastastat and kidney function. From baseline to month 6, there was no statistically significant difference in migelastal arm and placebo arms between eGFR _CKD-EPI or mGFR _iohexol (mITT was appropriate).

The annual changes in eGFR _CKD-EPI and mGFR _iohexol (± SEM) were -0.30 ± 6.6 and -1.51 ± 1.33 mL, respectively, in patients with migalastat (up to mITT) for up to 24 months. /min/1.73 m ² . Male gender and higher baseline proteinuria were associated with higher annual reduction rates. There were no statistically significant differences in baseline levels or changes from baseline between the treatment groups for 24-hour urine protein.

Migastastat and ultrasound cardiogram parameters. At baseline, the left ventricular mass index was comparable between the groups with no significant differences in the first phase.

A significant statistically significant decrease in left ventricular mass index (LVMi) was observed in patients who received migalastat for up to 24 months (ITT-adapted) (p < 0.05, based on 95% CI, excluding 0). Among them, patients with baseline LV hypertrophy were accompanied by a trend of greater decline. Table 3 shows the changes in ultrasound-cardiogram-derived LVMi from baseline to 18/24 months for patients with appropriate ITT. Table 3 : LVMi changes ( ITT is suitable)

The thickness of the septal wall was reduced by 0.061 cm ± 0.051 (5.2%) from baseline (1.17 cm ± 0.057) (95% CI: -1.67, 0.045); the thickness of the posterior wall of the left ventricle was stable for up to 24 months. Changes in left ventricular mass index were associated with changes in IVSWT (R ² = 0.26, p = 0.006), but were independent of changes in left ventricular posterior wall thickness (R ² = 0.06, p = 0.230).

In the extension of this study, LVMi continued to decline during the 30/36 months of migalastat treatment, with an average change from baseline of -17.0 g/m ² ([95% CI -26.2,-7.9]; = 15). In patients with baseline LVH (n = 11), the change from baseline was greater and was statistically -20.8 g/m ² [-95% CI -57.9, -2.2]. The LVMi changes after methalastat therapy from baseline to 6/12, 18/24, and 30/36 months are shown in Figure 3. When the study was extended to 30/36 months, 82% (9/11) and 46% (5/11) of baseline LVH patients had a reduction and normalization of LVMi, respectively.

Gastrointestinal Symptom Rating Scale. As shown in Table 4 below, 3 of the 5 areas of gastrointestinal symptoms (diarrhea, reflux, indigestion) were improved in patients with suitable ITT treated with migalastat.

For the diarrheal field, there was a statistically significant decrease between baseline and 6 months (Phase 1) (p = 0.03; ITT was appropriate); for patients with appropriate ITT with baseline symptoms, an insignificant observation was also observed. Falling (p = 0.06). Statistically significant changes were found within 24 months for patients with appropriate ITT and those with appropriate baseline ITT (p < 0.05, based on 95% CI, excluding 0).

In patients with appropriate ITT with baseline symptoms, there was a statistically significant improvement in the reflux phase in stage 1, (p = 0.047). Statistically significant changes were found in the field of dyspepsia within 24 months for patients with appropriate ITT and ITT-adapted patients with baseline symptoms (p < 0.05, based on 95% CI, excluding 0). There is an improvement trend in the field of constipation. Table 4 : Changes in the Gastrointestinal Symptom Rating Scale ¹ ( ITT- fit) * Indicates significant changes from baseline or significant changes in the boundary line. ¹ The least squares mean of changes from baseline ( BL ) | ² p = 0.03 and ³ using ANCOVA p = 0.047| ⁴ statistically significant or ⁵ based on a 95% CI trend with an upper limit of 0 .

Megastat and podocyte GL-3. Stereotactic electron microscopy studies by masking, at baseline and after 6 months of migalastat treatment, from ERT with a GLA mutation (N = 8) with migrating migalastat A kidney biopsy sample taken from a male patient with Fabry disease. The mean ± SD total volume V (Inc/Pc) of GL-3 inclusions in each podocyte of all patients decreased from 2568 ± 1408 μm ³ at baseline to 1282 ± after 6 months of migalastat. 792 μm ³ (p = 0.0182), as shown in Figure 4. Therefore, the drop in V(Inc/PC) is about 50%. The mean reduction in mean podocyte volume was from 6680 ± 2835 μm ³ at baseline to 3525 ± 2084 μm ³ (p = 0.004) after 6 months of migalastat (r = 0.98, p = 0.00003), eg Figure 5 shows. Therefore, the average podocyte volume decline is approximately 47%. These findings indicate that podocyte cytoplasmic contraction is directly proportional to GL-3 loss; therefore, there is no significant change in the volume fraction of podocyte cytoplasm due to GL-3. The magnitude of DG-3 volume reduction after gagasta was associated with an improvement in the width of the foot (r = 0.82, p = 0.02), as shown in Figure 6. Mean plasma hemolysis GB3 also decreased from 118 ± 48 nM at baseline to 75 ± 42 nM after 6 months of migalastat (p = 0.0004), as shown in Figure 7. This decrease was associated with a decrease in the percentage of podocyte GL-3 volume (r = 0.79, p = 0.02). As shown in Figure 8, there was a trend between a decrease in podocyte GL-3 volume and proteinuria (r = 0.69, p = 0.06) after 6 months of treatment with migalastat, but this reduction was found and Glomerular filtration rate is irrelevant. In the present study, migalastat treatment was associated with loss of GL-3 content in podocytes of patients with Fabry disease. The sensitive quantitative method used can assess the therapeutic effect on this important cell type in a relatively short period of time. This method is also more sensitive than other methods, including the method previously used in the Phase 2 study and the first method described above for qualitative assessment of podocyte GL-3 as described in this example.

Safety and adverse events. In the first phase, treatment for sudden adverse events was similar between groups. High-frequency adverse events in patients receiving migalastat were headache (12/34 patients - 35% vs 7/33 patients - 21%) and nasopharyngitis (6/34 patients) compared with placebo -18% vs. 2/34-6%). The most common adverse events reported by patients in stage 2 were headache (9/63 patients - 14%) and operational pain (7/63 patients - 11%, associated with renal biopsy), and the most common reports of non-blind extension Adverse events were proteinuria (9/57 patients - 16%), headache (6/57 patients - 11%), and bronchitis (6/57 patients - 11%). The severity of most adverse events is mild or moderate. No adverse events led to the interruption of milzastat.

Six patients had serious adverse events in stage 1 (2: migalastat; 4: placebo), 5 patients had serious adverse events in phase 2, and 11 patients experienced serious adverse events during non-blind extension . Two serious adverse events (fatigue and paresthesia) were assessed by the respondents as potentially related to milzastat. Both occurred on the same patient between the 12th and 24th months and have been resolved. No serious adverse events were reported by > 1 patient. Two patients discontinued migalastat due to serious adverse events; both were considered unrelated to migstatin. No deaths were reported.

Nine patients (16%) developed treatment for sudden proteinuria between the 12th and 24th months, and one of them was judged to be associated with migalastat. Of the 5 patients, the values for 24 months were the same as the baseline. Three patients with appropriate mutations had significant baseline proteinuria (> 1 g/24-hr), which increased within 24 months. Of the 28 patients with baseline proteinuria < 300 mg/24-h, 23 of the 24-hour urine protein remained stable during the migalastat treatment.

No progress as defined by Banikazemi et al. to end stage renal disease, cardiac death or stroke. There was a case of transient ischemic attack - judged to be unrelated to migalastat.

Analysis of vital signs, physical findings, laboratory and ECG parameters did not reveal the clinical relevance of migalastat. Example 2 : Administration of a dosage regimen for Fabry patients who have undergone ERT using migalastat hydrochloride

This example describes a Phase 3 study of migalastat therapy in Fabry patients who have undergone ERT.

The patient was selected. Eligible patients are 16-74 years old and have genetically proven Fabry disease; receive ERT ≥ 12 months; based on the human embryonic kidney-293 (HEK) assay used at the time of enrollment, have a response that will produce A GLA mutation in the mutant protein of migalastat; having an eGFR ≥ 30 ml/min/1.73 m ² ; and having an ERT dose level and regimen that has remained stable for at least 3 months.

Research design. After the eligibility baseline assessment, 57 patients were randomized to 18 months of migalastat therapy or ERT followed by 12 months of migalastat therapy (ATTRACT study; AT1001-012/NCT01218659). The migalastat dosing regimen is 150 mg of migalastat hydrochloride every other day. The primary objective was to compare the effects of migalastat on renal function relative to ERT, which was assessed by mGFR _iohexol after 18 months of treatment. Secondary goals are compared to ERT, the effect of milagist on the following: renal function (assessed by eGFR and 24-hour urine protein); comprehensive clinical outcome (by kidney, heart, cerebrovascular event or death) Time to evaluate); cardiac function (assessed by ultrasound cardiography) and patient reported results (pain and quality of life). result

Migastastat and ultrasound cardiogram parameters. This study of patients who have experienced ERT found that migalastat therapy reduced LVMi. At the 18th month, the mean change from baseline for migalastat and ERT was -6.6 g/m ² (95% CI -11.0, -2.1; n = 31) and -2.0 g/m ² (95%) CI -11.0, 7.0; n = 13). At baseline, LVMi changes from baseline to 18 months for militastat and ERT were -8.4 g/m ² (95% CI: -15.7, 2.6; n = 13) and 4.5 g/, respectively. m ² (95% CI: -10.7, 18.4; n = 5).

Patients treated with migalastat continued to show a decrease in LVMi at the 30th month (-3.8 g/m ² [95% CI -8.9, 1.3]; N = 30). A greater reduction was seen in patients with baseline LVH (n = 13), and the change from baseline after 30 months of migalastat therapy was -9.0 g/m ² . In Fabry patients with baseline LVH, 85% (11/13) had a LVMi decrease after 30 months of migalastat therapy, and 31% (4/13) had LVMi normalization. Example 3 Comparison of migalastat dosing regimens for treatment of Brucellosis

This example describes a second phase of a series of migalastat treatments in Fabry patients.

A series of doses and protocols were explored in 27 subjects (18 males and 9 females) in five Phase II studies: • 25 mg, 100 mg, and 250 mg twice daily (BID) Migaseta hydrochloride; • 50 mg of migalastat hydrochloride once daily (QD); • 50 mg, 150 mg, and 250 mg of migalastat salt every other day (QOD) Acid salt; and • 3 days dosing, 250 mg and 500 mg of migalastat hydrochloride per day, no dosing for 4 days.

In summary, nine different combinations of dosing amounts and dosing regimens were studied in these Phase 2 studies. Fabry disease is a rare hereditary disease, and because of the limited number of patient populations and study samples for this rare disease, some of the doses and protocols that will be explored are compared within the subject or across subjects. While others are compared across studies. These five Phase 2 studies were designed to assess the safety, pharmacokinetics, and pharmacodynamics of migalastat hydrochloride, with a focus on measuring white blood cell (WBC) alpha-Gal A activity and urinary GL-3 reduction to assess The efficacy of different doses and regimens. WBC α-Gal A activity provides reproducible minimally invasive measurements of the increased magnitude of enzymatic activity associated with different doses of migalastat hydrochloride, and is infrequently evaluated, invasive with enzyme activity in the skin and kidney Measurement related. Urinary GL-3 provides a reproducible minimally invasive measurement of GL-3 breakdown in the lysosome (the penultimate step in the mechanism of action pathway).

In these Phase 2 studies, every other day (QOD) of 150 mg resulted in the greatest decrease in urinary GL-3 in subjects with migalastat-responsive mutations, and was generally well tolerated. The urinary GL-3 levels of the QOD protocol are shown in Figures 9 and 10, and the arrows indicate 8 patients who received the 150 mg QOD protocol and had a compliant mutation according to the HEK-293 cell based assay.

In one of the Phase 2 studies, migalastat hydrochloride was administered to patients according to the following dosing schedule: 25 mg BID for the first two weeks; 100 mg BID for weeks 2-4; weeks 4-6, 200 mg BID; weeks 6-12, 25 mg BID; and 50 mg daily administration of the study was extended to week 96 as appropriate. The urine GL-3 results of this study are shown in Table 5 below. Table 5 : Urine GL-3

Administration of two doses of 25 mg, 100 mg, and 250 mg twice daily resulted in an increase in α-Gal A activity. It is expected that an increase in α-Gal A activity has a positive therapeutic effect (for example, a decrease in accumulation of the enzyme substrate GL-3). Unexpectedly, Table 5 above shows that there is an increase in urinary GL-3 in most subjects in the BID regimen, indicating a possible negative effect. This increase in urinary GL-3 may be due to high frequency dose intervals. When the subjects in the BID regimen switched to 50 mg per day, some patients showed a reduction in urinary GL-3, but the results were inconsistent for all patients. Although pharmacokinetic modeling indicates a dose of 50 mg per day, an exposure trough below IC ₅₀ (ie below inhibition) should be provided, but urinary GL-3 does not decrease as consistently as in 150 mg QOD. . By comparing Figures 9 and 10 with Table 5, 150 mg of QOD provides a much larger and more consistent reduction in urinary GL-3 compared to daily dosing or twice daily dosing.

Further research aimed to explore the possibility that a more frequent administration of a higher dose of migalastat may provide a greater reduction in substrate than a regimen of 150 mg administered every other day. Subjects were switched from 150 mg of migalastat hydrochloride QOD to 250 mg ("drug" period) once daily for 3 consecutive days, followed by 4 days without administration ("drug withdrawal" period) for 8 weeks And then 500 mg (administered for 3 days, not administered for 4 days) for at least 8 weeks. A small number of subjects showed elevated levels of WBC α-Gal A at higher doses; however, some subjects also showed signs of elevated urinary GL-3. As shown in Table 6 below, mean and median urinary GL-3 levels were elevated after subjects switched from 150 mg QOD to 250 mg and 500 mg (3 days dosing, 4 days do not administer). Then, when the subjects switched back to 150 mg QOD, the mean and median urine GL-3 fell back. In addition, some subjects cannot tolerate higher doses. Table 6 : Urine GL-3

Based on the results of these studies, every other day of administration provided an unexpected benefit that would not exist once a day or twice a day. In particular, every other day of administration resulted in the most consistent reduction in urinary GL-3 in subjects with migalastat responsive mutations. In fact, many other dosing regimens actually result in an increase in urinary GL-3. Dosing every other day resulted in a more consistent decrease in urinary GL-3 compared to 3 days of dosing and 4 days of no dosing, and some of the patients who received 3 days of dosing and 4 days of dosing did not. Shows the rise of urine GL-3. Recovery to 150 mg QOD after 3 days of dosing and 4 days of no dosing reduced mean and median urinary GL-3 levels.

The embodiments described herein are intended to illustrate the present compositions and methods, and are not intended to limit the scope of the invention. It is intended to include various modifications and changes that are consistent with the description as a whole and are readily understood by those skilled in the art. The scope of the appended claims should not be limited by the specific embodiments shown in the examples, but should be given the broadest interpretation consistent with the description as a whole.

Throughout this application, patents, patent applications, publications, product descriptions, gene bank accession numbers, and experimental protocols are cited, which are hereby incorporated by reference in its entirety for all purposes.

no

Other features of the present invention will become apparent from the following written description and drawings, in which:

Figures 1A-E show the complete DNA sequence of the human wild-type GLA gene (SEQ ID NO: 1).

Figure 2 shows the wild type a-Gal A protein (SEQ ID NO: 3).

Figure 3 shows the mean LVMi changes after migalastat therapy from baseline to 6/12, 18/24 and 30/36 months as described in Example 1.

Figure 4 shows individual changes in GL-3 inclusion volume per foot cell after migalastat treatment from baseline to 6 months as described in Example 1; (B) at baseline, from Glomerular disease in patients with Fabry disease and (C) glomeruli after 6 months of treatment.

Figure 5 shows (A) individual changes in podocyte volume after migalastat treatment from baseline to 6 months as described in Example 1; (B) podocyte volume and podocyte content after 6 months of treatment Correlation between volume of matter; (C) Volume fraction of GL-3 content in podocytes (foot pod volume/podocyte volume) at baseline and after 6 months of treatment.

Figure 6 shows the average width of the foot processes of patients with Fabry disease after baseline or 6 months of migalastat treatment as compared to 9 healthy controls as described in Example 1; (B) Correlation between changes in the width of the foot process and changes in the volume of GL-3 inclusions per podocyte.

Figure 7 shows individual changes in plasma hemolysis GB3 after migalastat treatment from baseline to 6 months as described in Example 1; changes in plasma hemolysis GB3 and (B) within GL-3 in podocytes Individual comparison between changes in volume fraction of the inclusions and changes in the volume of (C) GL-3 inclusions.

Figure 8 shows an independent comparison of 24 hour urine protein changes as (A) volume fraction changes of GL-3 inclusions in podocytes and (B) GL-3 inclusion volume as described in Example 1.

Figure 9 shows urinary GL-3 levels in female patients in migalastat therapy as described in Example 3.

Figure 10 shows urinary GL-3 levels in male patients in migalastat therapy as described in Example 3.

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Claims (200)

A method of reducing left ventricular mass index (LVMi) in a patient suffering from Fabry disease who has undergone enzyme replacement therapy (ERT), the method comprising administering to the patient an effective amount of migalastat every other day Or a formulation of a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 1, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of migalstat or a salt thereof. The method of claim 1 or 2, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any of claims 1-3, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any one of claims 1 to 3, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any one of claims 1 to 5, wherein the formulation comprises an oral dosage form. The method of claim 6, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any of claims 1-7, wherein migalstat or a salt thereof is administered for at least 18 months. The method of any of claims 1-8, wherein migalstat or a salt thereof is administered for at least 30 months. The method of any one of claims 1-9, wherein after administration of miggasstat or a salt thereof for 18 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients who have undergone ERT The average reduction of LVMi at 5 g/m ² was observed. The method of any one of claims 1 to 10, wherein after administration of miggasstat or a salt thereof for 18 months, administration of miggasstat or a salt thereof provides about 6.6 of a patient group that has undergone ERT The average of LVMi of g/m ² is reduced. The method of any one of claims 1 to 11, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients who have undergone ERT The average of LVMi of 2 g/m ² was reduced. The method of any one of claims 1 to 12, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides about 3.8 of a patient group that has undergone ERT The average of LVMi of g/m ² is reduced. The method of any one of claims 1 to 13, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides at least at least one of the LVH patient groups that have undergone ERT The average reduction of LVMi of about 5 g/m ² was observed. The method of any one of claims 1 to 14, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides about an LVH patient group that has undergone ERT The average reduction of LVMi at 9 g/m ² was observed. A method of reducing left ventricular mass index (LVMi) in a patient with Fabry disease who is initially treated with an enzyme replacement therapy (ERT), the method comprising administering to the patient an effective amount of migalastat every other day Or a formulation of a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 16, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of migalstat or a salt thereof. The method of claim 16 or 17, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any of claims 16-18, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any of claims 16-18, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any of claims 16-20, wherein the formulation comprises an oral dosage form. The method of claim 21, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any of claims 16-22, wherein miggasstat or a salt thereof is administered for at least 18 months. The method of any one of claims 16 to 23, wherein migalstat or a salt thereof is administered for at least 30 months. The method of any one of claims 16-24, wherein after administration of miggasstat or a salt thereof for 18 to 24 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average decrease in LVMi of at least about 5 g/m ² . The method of any one of claims 16 to 25, wherein after administration of miggasstat or a salt thereof for 18 to 24 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average reduction of LVMi was about 7.7 g/m ² . The method of any one of claims 16 to 26, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average decrease in LVMi of at least about 10 g/m ² . The method of any one of claims 16 to 27, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average reduction of LVMi of about 17 g/m ² was observed. The method of any one of claims 16 to 28, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of LVH patients who have been initially treated with ERT The average decrease in LVMi of at least about 15 g/m ² . The method of any one of claims 16 to 29, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of LVH patients initially treated with ERT The average reduction of LVMi was about 20.8 g/m ² . A method of normalizing a left ventricular mass index (LVMi) in a patient suffering from Fabry disease, the method comprising administering to the patient an formulation comprising an effective amount of migalastat or a salt thereof, every other day, wherein The effective amount is about 123 mg of free base equivalent (FBE). The method of claim 31, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of migalstat or a salt thereof. The method of claim 31 or 32, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any of claims 31-33, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any of claims 31-33, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any of claims 31-35, wherein the formulation comprises an oral dosage form. The method of claim 36, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any of claims 31-37, wherein miggasstat or a salt thereof is administered for at least 18 months. The method of any of claims 31-38, wherein miggasstat or a salt thereof is administered for at least 30 months. A method of normalizing a left ventricular mass index (LVMi) in a patient with Fabry disease who has undergone enzyme replacement therapy (ERT), the method comprising administering to the patient an effective amount of MiGasi every other day A formulation of the same or a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 40, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of miggasstat or a salt thereof. The method of claim 40 or 41, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any one of claims 40-42, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any one of claims 40-42, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any of claims 40-44, wherein the formulation comprises an oral dosage form. The method of claim 45, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any of claims 40-46, wherein miggasstat or a salt thereof is administered for at least 18 months. The method of any of claims 40-47, wherein miggasstat or a salt thereof is administered for at least 30 months. The method of any one of claims 40 to 48, wherein after administration of miggasstat or a salt thereof for 18 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients who have undergone ERT The average reduction of LVMi at 5 g/m ² was observed. The method of any one of claims 40-49, wherein after administration of miggasstat or a salt thereof for 18 months, administration of miggasstat or a salt thereof provides about 6.6 of a patient group that has undergone ERT The average of LVMi of g/m ² is reduced. The method of any one of claims 40 to 50, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients who have undergone ERT The average of LVMi of 2 g/m ² was reduced. The method of any one of claims 40-51, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides about 3.8 of a patient group that has undergone ERT The average of LVMi of g/m ² is reduced. The method of any one of claims 40-52, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides at least at least one of the LVH patient groups that have undergone ERT The average reduction of LVMi of about 5 g/m ² was observed. The method of any one of claims 40-53, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides about an LVH patient group that has undergone ERT The average reduction of LVMi at 9 g/m ² was observed. A method of normalizing enzyme replacement therapy (ERT) for the treatment of left ventricular mass index (LVMi) in patients with Fabry disease, the method comprising administering to the patient an effective amount of MiGasi every other day A formulation of the same or a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 55, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of migalstat or a salt thereof. The method of claim 55 or 56, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any one of claims 55-57, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any of claims 55-57, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any of claims 55-59, wherein the formulation comprises an oral dosage form. The method of claim 60, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any of claims 55-61, wherein miggasstat or a salt thereof is administered for at least 18 months. The method of any of claims 55-62, wherein miggasstat or a salt thereof is administered for at least 30 months. The method of any one of claims 55-63, wherein after administration of miggasstat or a salt thereof for 18 to 24 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average decrease in LVMi of at least about 5 g/m ² . The method of any one of claims 55-64, wherein after administration of miggasstat or a salt thereof for 18 to 24 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average reduction of LVMi was about 7.7 g/m ² . The method of any one of claims 55-65, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average decrease in LVMi of at least about 10 g/m ² . The method of any one of claims 55-66, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average reduction of LVMi of about 17 g/m ² was observed. The method of any one of claims 55-67, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of LVH patients initially treated with ERT The average decrease in LVMi of at least about 15 g/m ² . The method of any one of claims 55-68, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of LVH patients initially treated with ERT The average reduction of LVMi was about 20.8 g/m ² . A method of reducing podocyte neuropterin trihexosides (GL-3) in a patient suffering from Fabry disease, the method comprising administering to the patient an effective amount of migalastat or a salt thereof every other day The formulation wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 70, wherein the migaster or a salt thereof enhances α-galactosidase A activity. The method of claim 70 or 71, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of claim 70 or 71, wherein about 150 mg of migalastat hydrochloride is administered to the patient every other day. The method of any one of claims 70-73, wherein the formulation comprises an oral dosage form. The method of claim 74, wherein the oral dosage form comprises a tablet, capsule or solution. The method of any one of claims 70-75, wherein migalstat or a salt thereof is administered for at least 6 months. The method of any one of claims 70-76, wherein the patient is an ERT initial patient. The method of any one of claims 70-76, wherein the patient is a patient who has undergone ERT. A method of reducing podocyte volume in a patient suffering from Fabry disease, the method comprising administering to the patient an formulation comprising an effective amount of migalastat or a salt thereof every other day, wherein the effective amount is about 123 mg free base equivalent (FBE). The method of claim 79, wherein the migaster or a salt thereof enhances α-galactosidase A activity. The method of claim 79 or 80, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of claim 79 or 80, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any one of claims 79-82, wherein the formulation comprises an oral dosage form. The method of claim 83, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any of claims 79-84, wherein miggasstat or a salt thereof is administered for at least 6 months. The method of any one of claims 79-85, wherein after administration of miggasstat or a salt thereof for 6 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients with an initial ERT The average volume of podocytes in 30% decreased. The method of any one of claims 79-86, wherein after administration of miggasstat or a salt thereof for 6 months, administration of miggasstat or a salt thereof provides about 47 of the group of patients with initial ERT The average decrease in % podocyte volume. The method of any one of claims 79-87, wherein the patient is an ERT initial patient. The method of any one of claims 79-87, wherein the patient is a patient who has undergone ERT. A method of reducing the volume of a neuropterin trihexose glycoside (GL-3) inclusion in each podocyte of a patient suffering from Fabry disease, the method comprising administering to the patient an effective amount each other every other day A formulation of migaster or a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 90, wherein the migaster or a salt thereof enhances α-galactosidase A activity. The method of claim 90 or 91, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of claim 90 or 91, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any one of claims 90-92, wherein the formulation comprises an oral dosage form. The method of claim 94, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any one of claims 90-95, wherein miggasstat or a salt thereof is administered for at least 6 months. The method of any one of claims 90 to 96, wherein after administration of miggasstat or a salt thereof for 6 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients with ERT initial treatment The 30% GL-3 inclusion volume decreased on average per foot. The method of any one of claims 90-97, wherein after administration of miggasstat or a salt thereof for 6 months, administration of miggasstat or a salt thereof provides about 50 of the group of patients with initial ERT The % GL-3 inclusion volume decreased on average per foot of cells. The method of any one of claims 90-98, wherein the patient is an ERT initial patient. The method of any one of claims 90-98, wherein the patient is a patient who has undergone ERT. A method of treating a Fabry-Perfect patient who has undergone enzyme replacement therapy (ERT) by reducing left ventricular mass (LVM), the method comprising administering to a patient in need thereof an effective amount of MiGasi every other day A formulation of the same or a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 101, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of migalstat or a salt thereof. The method of claim 101 or 102, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any of claims 101-103, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any of claims 101-103, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any of claims 101-105, wherein the formulation comprises an oral dosage form. The method of claim 106, wherein the oral dosage form comprises a tablet, capsule or solution. The method of any of claims 101-107, wherein miggasstat or a salt thereof is administered for at least 18 months. The method of any of claims 101-108, wherein miggasstat or a salt thereof is administered for at least 30 months. The method of any one of claims 101-109, wherein after administration of miggasstat or a salt thereof for 18 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients who have undergone ERT The mean decrease in left ventricular mass index (LVMi) of 5 g/m ² . The method of any one of claims 101-110, wherein after administration of miggasstat or a salt thereof for 18 months, administration of miggasstat or a salt thereof provides about 6.6 of a patient group that has undergone ERT The average of LVMi of g/m ² is reduced. The method of any one of claims 101-111, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients who have undergone ERT The average of LVMi of 2 g/m ² was reduced. The method of any of claims 101-112, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides about 3.8 of a patient group that has undergone ERT The average of LVMi of g/m ² is reduced. The method of any one of claims 101-113, wherein, after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides at least at least one of the LVH patient groups that have undergone ERT The average reduction of LVMi of about 5 g/m ² was observed. The method of any one of claims 101 to 114, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides about an LVH patient group that has undergone ERT The average reduction of LVMi at 9 g/m ² was observed. A method of treating a newly prepared Fabry patient in an enzyme replacement therapy (ERT) by reducing left ventricular mass (LVM), the method comprising administering to a patient in need thereof an effective amount of MiGasi every other day A formulation of the same or a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 116, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of miggasstat or a salt thereof. The method of claim 116 or 117, wherein the migaster or a salt thereof enhances α-galactosidase A activity. The method of any one of claims 116-118, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any one of claims 116-118, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any of claims 116-120, wherein the formulation comprises an oral dosage form. The method of claim 121, wherein the oral dosage form comprises a tablet, capsule or solution. The method of any one of claims 116-122, wherein migalstat or a salt thereof is administered for at least 18 months. The method of any of claims 116-123, wherein migalstat or a salt thereof is administered for at least 30 months. The method of any one of claims 116-124, wherein after administration of miggasstat or a salt thereof for 18 to 24 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average reduction in left ventricular mass index (LVMi) of at least about 5 g/m ² . The method of any one of claims 116-125, wherein after administration of miggasstat or a salt thereof for 18 to 24 months, administration of miggasstat or a salt thereof provides a group of patients with an initial treatment of ERT The average reduction of LVMi was about 7.7 g/m ² . The method of any one of claims 116 to 126, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average decrease in LVMi of at least about 10 g/m ² . The method of any one of claims 116-127, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of patients with initial ERT The average reduction of LVMi of about 17 g/m ² was observed. The method of any one of claims 116-128, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of LVH patients initially treated with ERT The average decrease in LVMi of at least about 15 g/m ² . The method of any one of claims 116-129, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of LVH patients with initial ERT treatment The average reduction of LVMi was about 20.8 g/m ² . A method of treating a Fabry patient by normalizing a left ventricular mass index (LVMi), the method comprising administering to a patient in need thereof a formulation comprising an effective amount of migalastat or a salt thereof every other day. Wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 131, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of migalstat or a salt thereof. The method of claim 131 or 132, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any one of claims 131-133, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any one of claims 131-133, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any one of claims 131-135, wherein the formulation comprises an oral dosage form. The method of claim 136, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any one of claims 131-137, wherein miggasstat or a salt thereof is administered for at least 18 months. The method of any of claims 131-138, wherein migalstat or a salt thereof is administered for at least 30 months. A method of treating a Fabry-Perfect patient who has undergone enzyme replacement therapy (ERT) by normalizing the left ventricular mass index (LVMi), which comprises administering to a patient in need thereof an effective amount of rice every other day. A formulation of gastrostat or a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 140, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of migalstat or a salt thereof. The method of claim 140 or 141, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any one of claims 140-142, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any one of claims 140-142, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any one of claims 140-144, wherein the formulation comprises an oral dosage form. The method of claim 145, wherein the oral dosage form comprises a tablet, capsule or solution. The method of any one of claims 140-146, wherein migalstat or a salt thereof is administered for at least 18 months. The method of any one of claims 140-147, wherein miggasstat or a salt thereof is administered for at least 30 months. The method of any one of claims 140-148, wherein after administration of miggasstat or a salt thereof for 18 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients who have undergone ERT The average reduction of LVMi at 5 g/m ² was observed. The method of any one of claims 140-149, wherein after administration of miggasstat or a salt thereof for 18 months, administration of miggasstat or a salt thereof provides about 6.6 of a patient group that has undergone ERT The average of LVMi of g/m ² is reduced. The method of any one of claims 140-150, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients who have undergone ERT The average of LVMi of 2 g/m ² was reduced. The method of any one of claims 140-151, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides about 3.8 of a patient group that has undergone ERT The average of LVMi of g/m ² is reduced. The method of any one of claims 140-152, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides at least at least one of the LVH patient groups that have undergone ERT The average reduction of LVMi of about 5 g/m ² was observed. The method of any one of claims 140-153, wherein after administration of miggasstat or a salt thereof for 30 months, administration of miggasstat or a salt thereof provides for an LVH patient group that has undergone ERT The average reduction of LVMi at 9 g/m ² was observed. A method of treating a Fabry-Presence patient with an initial treatment for enzyme replacement therapy (ERT) by normalizing the left ventricular mass index (LVMi), which comprises administering to a patient in need thereof an effective amount of rice every other day. A formulation of gastrostat or a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 155, wherein the patient has left ventricular hypertrophy (LVH) prior to initiating administration of migalstat or a salt thereof. The method of claim 155 or 156, wherein the migalastat or a salt thereof enhances α-galactosidase A activity. The method of any one of claims 155-157, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of any one of claims 155-157, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any one of claims 155-159, wherein the formulation comprises an oral dosage form. The method of claim 160, wherein the oral dosage form comprises a tablet, capsule or solution. The method of any of claims 155-161, wherein migalstat or a salt thereof is administered for at least 18 months. The method of any one of claims 155-162, wherein miggasstat or a salt thereof is administered for at least 30 months. The method of any one of claims 155-163, wherein after administration of miggasstat or a salt thereof for 18 to 24 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average decrease in LVMi of at least about 5 g/m ² . The method of any one of claims 155-164, wherein after administration of miggasstat or a salt thereof for 18 to 24 months, administration of miggasstat or a salt thereof provides a group of patients with initial ERT The average reduction of LVMi was about 7.7 g/m ² . The method of any one of claims 155-165, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average decrease in LVMi of at least about 10 g/m ² . The method of any one of claims 155-166, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of patients in the initial treatment of ERT The average reduction of LVMi of about 17 g/m ² was observed. The method of any one of claims 155-167, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of LVH patients initially treated with ERT The average decrease in LVMi of at least about 15 g/m ² . The method of any one of claims 155-168, wherein after administration of miggasstat or a salt thereof for 30 to 36 months, administration of miggasstat or a salt thereof provides a group of LVH patients initially treated with ERT The average reduction of LVMi was about 20.8 g/m ² . A method of treating Fabry's patients by reducing podocyte neuropterin trihexosides (GL-3), which comprises administering to a patient in need thereof an effective amount of migalastat or every other day. A formulation of a salt thereof wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 70, wherein the migaster or a salt thereof enhances α-galactosidase A activity. The method of claim 70 or 71, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of claim 70 or 71, wherein about 150 mg of migalastat hydrochloride is administered to the patient every other day. The method of any one of claims 70-73, wherein the formulation comprises an oral dosage form. The method of claim 74, wherein the oral dosage form comprises a tablet, capsule or solution. The method of any one of claims 70-75, wherein migalstat or a salt thereof is administered for at least 6 months. The method of any one of claims 70-76, wherein the patient is an ERT initial patient. The method of any one of claims 70-76, wherein the patient is a patient who has undergone ERT. A method of treating a Fabry patient by reducing the volume of the podocyte, the method comprising administering to a patient in need thereof a formulation comprising an effective amount of migalastat or a salt thereof, every other day, wherein the effective amount It is about 123 mg of free base equivalent (FBE). The method of claim 79, wherein the migaster or a salt thereof enhances α-galactosidase A activity. The method of claim 79 or 80, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of claim 79 or 80, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any one of claims 79-82, wherein the formulation comprises an oral dosage form. The method of claim 83, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any of claims 79-84, wherein miggasstat or a salt thereof is administered for at least 6 months. The method of any one of claims 79-85, wherein after administration of miggasstat or a salt thereof for 6 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients with an initial ERT The average volume of podocytes in 30% decreased. The method of any one of claims 79-86, wherein after administration of miggasstat or a salt thereof for 6 months, administration of miggasstat or a salt thereof provides about 47 of the group of patients with initial ERT The average decrease in % podocyte volume. The method of any one of claims 79-87, wherein the patient is an ERT initial patient. The method of any one of claims 79-87, wherein the patient is a patient who has undergone ERT. A method of treating a Fabry patient by reducing the volume of a neuropterin trihexosides (GL-3) inclusion per foot cell, the method comprising administering to a patient in need thereof every other day effective An amount of a formulation of migaster or a salt thereof, wherein the effective amount is about 123 mg of free base equivalent (FBE). The method of claim 90, wherein the migaster or a salt thereof enhances α-galactosidase A activity. The method of claim 90 or 91, wherein the patient is administered about 123 mg of migalastat free base every other day. The method of claim 90 or 91, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day. The method of any one of claims 90-92, wherein the formulation comprises an oral dosage form. The method of claim 94, wherein the oral dosage form comprises a tablet, a capsule or a solution. The method of any one of claims 90-95, wherein miggasstat or a salt thereof is administered for at least 6 months. The method of any one of claims 90 to 96, wherein after administration of miggasstat or a salt thereof for 6 months, administration of miggasstat or a salt thereof provides at least about at least about a group of patients with ERT initial treatment The 30% GL-3 inclusion volume decreased on average per foot. The method of any one of claims 90-97, wherein after administration of miggasstat or a salt thereof for 6 months, administration of miggasstat or a salt thereof provides about 50 of the group of patients with initial ERT The % GL-3 inclusion volume decreased on average per foot of cells. The method of any one of claims 90-98, wherein the patient is an ERT initial patient. The method of any one of claims 90-98, wherein the patient is a patient who has undergone ERT.