Methods of treating Fabry patients having renal impairment
Inventors
Castelli, Jeff • Benjamin, Elfrida
Assignees
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Publication Number
US-12042489-B2
Publication Date
2024-07-23
Expiration Date
Abstract
Provided are methods for treatment of Fabry disease in patients having HEK assay amenable mutations in α-galactosidase A. Certain methods comprise administering migalastat or a salt thereof every other day, such as administering about 150 mg of migalastat hydrochloride every other day.
Core Innovation
The invention relates to molecules comprising migalastat bound to an alpha-galactosidase A protein having a HEK assay amenable mutation. The HEK assay amenable mutation is selected from a specified group of amino-acid substitutions and variants, including A13T, N34T, M42K, L54F, P60T, E87D, L89F, Y123C, H125L, I133M, K140T, F145S, P146R, Y152H, D165G, p.M187_S188dup, V199G, M208R, I219L, N224T, Q250R, G261C, G271D, M284V, I303F, D322N, G325R, K326N, G334E, E358Q, E358D, G361E, G375E, T412N, and M421V.
In another aspect, the invention provides an alpha-galactosidase A protein that is bound to migalastat and has increased stability compared to a naturally-occurring alpha-galactosidase A protein having the same mutation. The increased-stability protein is defined using a HEK amenable mutation selected from the same specified group.
In a treatment aspect, the invention provides a method of treating Fabry disease by administering migalastat to a patient in need thereof. The patient is defined as having an alpha-galactosidase A protein comprising a HEK assay amenable mutation selected from the specified group of amino-acid substitutions and variants.
Claims Coverage
The document provides three independent claims. Their inventive features focus on migalastat bound to an alpha-galactosidase A protein containing a specified HEK assay amenable mutation set, a migalastat-bound alpha-galactosidase A protein with increased stability versus naturally-occurring protein for the same mutation, and administering migalastat to treat Fabry disease in patients having alpha-galactosidase A with a specified HEK assay amenable mutation set.
Migalastat-bound alpha-galactosidase A with HEK assay amenable mutation set
A molecule comprising migalastat bound to an alpha-galactosidase A protein comprising a HEK assay amenable mutation selected from the group consisting of A13T, N34T, M42K, L54F, P60T, E87D, L89F, Y123C, H125L, I133M, K140T, F145S, P146R, Y152H, D165G, p.M187_S188dup, V199G, M208R, I219L, N224T, Q250R, G261C, G271D, M284V, I303F, D322N, G325R, K326N, G334E, E358Q, E358D, G361E, G375E, T412N and M421V.
Migalastat-bound alpha-galactosidase A with increased stability versus naturally-occurring protein
An alpha-galactosidase A protein having a HEK amenable mutation selected from the group consisting of A13T, N34T, M42K, L54F, P60T, E87D, L89F, Y123C, H125L, I133M, K140T, F145S, P146R, Y152H, D165G, p.M187_S188dup, V199G, M208R, I219L, N224T, Q250R, G261C, G271D, M284V, I303F, D322N, G325R, K326N, G334E, E358Q, E358D, G361E, G375E, T412N and M421V, wherein the protein is bound to migalastat and the protein has increased stability as compared to a naturally-occurring alpha-galactosidase A protein having the same mutation.
Administering migalastat to treat Fabry disease for HEK assay amenable mutations
A method of treating Fabry disease, the method comprising administering migalastat to a patient in need thereof, wherein the patient has an alpha-galactosidase A protein comprising a HEK assay amenable mutation selected from the group consisting of A13T, N34T, M42K, L54F, P60T, E87D, L89F, Y123C, H125L, I133M, K140T, F145S, P146R, Y152H, D165G, p.M187_S188dup, V199G, M208R, I219L, N224T, Q250R, G261C, G271D, M284V, I303F, D322N, G325R, K326N, G334E, E358Q, E358D, G361E, G375E, T412N and M421V.
Across the independent claims, the core coverage is directed to migalastat bound to alpha-galactosidase A proteins defined by a HEK assay amenable mutation set, including an increased stability property versus naturally-occurring protein for the same mutation, and to treating Fabry disease by administering migalastat to patients whose alpha-galactosidase A contains one of the specified HEK assay amenable mutations.
Stated Advantages
Reducing plasma lyso-Gb3.
Increasing WBC alpha-Gal A activity.
Reducing left ventricular mass index (LVMi).
Stabilizing renal function.
Reducing globotriaosylceramide (GL-3) accumulated in an organ of the patient.
Documented Applications
Treating Fabry disease in a patient having an alpha-galactosidase A protein comprising a HEK assay amenable mutation, by administering migalastat.
In therapeutic outcome characterizations, administration effective to reduce GL-3 accumulation in an organ, reduce plasma lyso-Gb3, increase WBC alpha-Gal A activity, reduce LVMi, and/or stabilize renal function.
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