Methods of treating Fabry patients having renal impairment

Inventors

Castelli, Jeff • Benjamin, Elfrida

Assignees

Amicus Therapeutics Inc

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 disclosure provides a method of treating Fabry disease by administering migalastat to a patient in need thereof. The patient has an α-galactosidase A protein comprising a HEK assay amenable mutation selected from a specified group of mutations, including amino-acid substitutions and named variants such as p.V254del and p.T400_S401dup. The approach selects patients based on HEK assay amenable mutation status and uses migalastat administration as the therapeutic intervention.

In addition, the disclosure defines a molecule comprising migalastat bound to an α-galactosidase A protein that includes a HEK assay amenable mutation selected from the same enumerated mutation group. The bound-molecule concept further includes dependent refinements that narrow the allowable mutation subsets to specific members from the overall enumerated list. The disclosure also includes α-galactosidase A protein compositions in which the protein is bound to migalastat and exhibits increased stability as compared to a naturally-occurring α-galactosidase A protein having the same mutation.

The described treatment and composition framework is also tied to claimed/expected clinical and pharmacodynamic outcomes in renal impairment settings in Fabry disease, using measures including renal function, plasma lyso-Gb3, and WBC α-Gal A activity. It additionally references cardiac tissue outcome measures such as left ventricular mass index. The patient population and outcome readouts are framed around the presence of HEK assay amenable mutations and the administration of migalastat, including consideration of migalastat salts such as migalastat hydrochloride.

Claims Coverage

The partial content includes three independent claims. Across these, the claims concentrate on patient selection and treatment using migalastat for Fabry disease with HEK assay amenable mutations, the chemistry/biological entity of migalastat bound to an HEK assay amenable α-galactosidase A variant, and increased stability of the migalastat-bound α-galactosidase A protein compared to a naturally-occurring counterpart with the same mutation. Overall, the inventive features are strongly defined by enumerated mutation sets and binding/stability relationships.

The independent claims collectively cover migalastat-based Fabry disease treatment that is restricted to patients with α-galactosidase A HEK assay amenable mutations from enumerated lists, a corresponding migalastat-bound α-galactosidase A molecule defined by the same mutation constraint, and an α-galactosidase A protein bound to migalastat that is defined by increased stability relative to a naturally-occurring protein carrying the same mutation. Dependent claims in the provided excerpts further narrow which specific mutations from the enumerated sets are eligible.

Stated Advantages

Documented Applications