Methods of treating Fabry patients having renal impairment
Inventors
Castelli, Jeff • Benjamin, Elfrida
Assignees
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Publication Number
US-12042488-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 a pharmacological chaperone migalastat for treating Fabry disease patients with renal impairment and/or elevated proteinuria. Migalastat, including salts such as migalastat hydrochloride, is provided in an oral dosing regimen once every other day. The dosing rationale is described in terms of pharmacological chaperones being renally cleared, such that renal impairment can affect needed dosing.
The disclosed approach includes stabilizing renal function, reducing left ventricular mass index (LVMi), reducing plasma lyso-Gb3, and increasing WBC α-Gal A activity, with effects reported in the context of mild/moderate renal impairment and supported by analyses by baseline renal function/proteinuria. The content further reports long-term stabilization outcomes associated with the described migalastat-containing regimen.
The disclosure also includes pharmacokinetic rationale and modeling/simulation comparing renal impairment exposure trends and Fabry versus non-Fabry trends, and reports pharmacokinetic study results in non-Fabry subjects and Fabry patients with renal impairment. In addition, the document addresses a migalastat-bound α-galactosidase A protein having HEK amenable mutations, as reflected in the claims, thereby tying the pharmacological chaperone concept to α-galactosidase A variants.
Claims Coverage
The partial claim set includes two independent claims directed to migalastat-bound α-galactosidase A proteins with specified HEK amenable mutations. Across the families, the main inventive coverage is binding of the α-galactosidase A protein to migalastat and selecting particular HEK amenable mutations, with some dependent claims further requiring increased stability versus a naturally occurring α-galactosidase A protein having the same mutation.
Migalastat-bound HEK amenable α-galactosidase A with selected mutations
An α-galactosidase A protein having a HEK amenable mutation selected from the group consisting of G334E, N34D and p.V254del, wherein the protein is bound to migalastat.
Migalastat-bound HEK amenable α-galactosidase A with N215I
An α-galactosidase A protein having a HEK amenable mutation N215I, wherein the protein is bound to migalastat.
The independent claims cover migalastat-bound α-galactosidase A proteins defined by HEK amenable mutations G334E, N34D, or p.V254del in one claim and N215I in another. The dependent-claim families reflected in the provided claim text further specify certain mutations and include a comparative requirement that the migalastat-bound, mutation-matched protein has increased stability versus a naturally occurring α-galactosidase A protein with the same mutation.
Stated Advantages
Stabilizing renal function in Fabry disease patients with renal impairment.
Reducing left ventricular mass index (LVMi).
Reducing plasma lyso-Gb3.
Increasing WBC α-Gal A activity.
Documented Applications
Treatment of Fabry disease patients with renal impairment and/or elevated proteinuria using oral pharmacological chaperone migalastat, including migalastat salts such as migalastat hydrochloride.
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