Methods of treatment for cystic fibrosis
Inventors
Chen, Weichao George • Haseltine, Eric L • Moskowitz, Samuel • Robertson, Sarah • Waltz, David
Assignees
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Publication Number
US-12350262-B2
Publication Date
2025-07-08
Expiration Date
Abstract
Compound I of the formula and/or pharmaceutically acceptable salt(s) of Compound I comprised in a pharmaceutical composition and methods of using the same to treat cystic fibrosis.
Core Innovation
The disclosed subject matter relates to cystic fibrosis treatment by administering to a patient in need thereof crystalline Form A of Compound I, amorphous Compound II, and amorphous Compound III. The regimen specifies once-daily dosing for Compound I and Compound II and twice-daily dosing for Compound III, with specified amounts in the claims.
The document further includes optional combination therapy using CFTR corrector Compound II and CFTR potentiator Compound III, with Compound III also described in deuterated form (Compound III-d) and/or a related benzoic acid Compound IV. The content characterizes these compounds by their roles in CFTR dysfunction and patient genotype subgrouping.
The disclosed material also includes formation of crystalline Form A of Compound I and an amorphous spray-dried dispersion associated with HPMCAS-HG, with solid-state characterization by XRPD and MDSC. Additional examples describe chemical synthesis and characterization for multiple intermediates and final small molecules, including a CF3-substituted pyrazole-containing scaffold and subsequent transformations leading to carboxamide/sulfonamide-type products.
Claims Coverage
The independent claims cover cystic fibrosis treatment using crystalline Form A of Compound I, amorphous Compound II, and amorphous Compound III, with specified once-daily and twice-daily dosing amounts. Dependent claims further add an additional Compound III dose administered 12 hours after the initial administration.
Crystalline form a compound i with once-daily dosing
Administering crystalline Form A of Compound I once daily as part of a cystic fibrosis treatment regimen.
Amorphous compound ii with once-daily dosing
Administering amorphous Compound II once daily as part of a cystic fibrosis treatment regimen.
Amorphous compound iii with twice-daily per-dose amount
Administering amorphous Compound III at a specified per-dose amount twice daily as part of a cystic fibrosis treatment regimen.
Additional compound iii dose after 12-hour interval
Repeating administration of an additional dose of amorphous Compound III 12 hours after an initial administration as a refinement of the twice-daily regimen.
Across the independent claims, the inventive subject matter is the treatment of cystic fibrosis by administering crystalline Form A of Compound I once daily, amorphous Compound II once daily, and amorphous Compound III twice daily at specified per-dose amounts; dependent claims further refine the schedule by administering an additional Compound III dose 12 hours after an initial administration.
Stated Advantages
Improvement in ppFEV1.
Improvement in sweat chloride.
Improvement in CFQ-R respiratory domain scores.
Reported safety/tolerability in cystic fibrosis clinical study results.
Decreases in sweat chloride.
Increases in ppFEV1.
Documented Applications
Treating cystic fibrosis by administering crystalline Form A of Compound I, amorphous Compound II, and amorphous Compound III according to specified dosing regimens.
Assessing F508del-CFTR modulator properties using an optical membrane potential assay and an Ussing chamber chloride transport assay.
Evaluating triple combinations of Compound I/II/III in cystic fibrosis clinical studies, including reported dosing regimens and outcomes such as ppFEV1, sweat chloride, and CFQ-R respiratory domain scores.
Treating cystic fibrosis in a patient in need thereof using CFTR-mediated cystic fibrosis treatment with Compound I, including crystalline Form A, optionally in combination with CFTR corrector Compound II and CFTR potentiator Compound III (including deuterated Compound III-d) and/or benzoic acid Compound IV.
Treatment of cystic fibrosis patients, including genotype categories defined by F508del/minimal function mutation panel, F508del/gating mutation panel, and F508del/residual function mutation panel, with an absolute change in ppFEV1 after 29 days of administration.
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