Spray-dried dispersions, formulations, and polymorphs of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide
Inventors
Brandhuber, Barbara J. • Brent, Lauren T. • Eary, Charles Todd • Kenna, Andrew • Khan, Firas • Renshaw, Vivian F. H. • Spencer, Stacey Renee
Assignees
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Publication Number
US-12268666-B2
Publication Date
2025-04-08
Expiration Date
Abstract
A spray-dried dispersions and pharmaceutical composition of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide, pharmaceutically acceptable salts thereof, or a combination thereof and the use of the spray-dried dispersion and pharmaceutical composition in the treatment of cancer and autoimmune and inflammatory diseases are disclosed. Also provided are crystalline forms of (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide also useful in the treatment of cancer and autoimmune and inflammatory diseases.
Core Innovation
The invention relates to a spray-dried dispersion comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, together with one or more polymers selected from an HPMCAS polymer, an HPMC polymer, a vinylpyrrolidone-vinyl acetate copolymer, and a polyvinylpyrrolidone (PVP) polymer. The disclosed concept includes selecting the polymer combination and the physical form of the compound in the dispersion, and the compound of Formula I is characterized as present in an amorphous form.
The spray-dried dispersion includes HPMCAS polymer as a defined polymer component, and the compound-to-polymer composition is constrained by defined ratio ranges for the compound of Formula I to the HPMCAS polymer, including about 1:4 to about 4:1. Further refinements specify HPMCAS subtypes selected from HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HPMCAS-HF, or HPMCAS-HG, including an embodiment where HPMCAS-MG is used.
The disclosure also describes detecting circulating tumor DNA (ctDNA) and/or cfDNA in a liquid biopsy to reflect dysregulation of BTK across one or multiple genes. The BTK-associated genetic alterations include point mutations, copy number variations, genetic fusions, and insertions/deletions, including germline and somatic variants, as well as BTK resistance mutations. The detected allele frequency changes over time are used to assess treatment efficacy and detect resistance development.
The disclosure links the liquid biopsy-based detection and monitoring to selecting and/or monitoring therapy with the compound of Formula I, including salts, amorphous form, polymorph form, and spray-dried dispersion. The therapy positioning includes combination and switching strategies involving BTK inhibitors and other anticancer agents, with adjunct mention of CAR-T/immunotherapy broadly, in the context of BTK dysregulation and resistance markers.
Claims Coverage
The document includes independent claim coverage directed to a spray-dried dispersion formulation and related BTK monitoring disclosures. The inventive features center on a compound of Formula I, or a pharmaceutically acceptable salt thereof, combined with one or more polymers selected from a defined group, with dependent claims narrowing the physical form, polymer selection, ratio, and HPMCAS subtype. The claims cover 6 inventive features.
Spray-dried dispersion with selected polymer group
A spray-dried dispersion comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more polymers selected from the group consisting of an HPMCAS polymer, an HPMC polymer, a vinylpyrrolidone-vinyl acetate copolymer, and a polyvinylpyrrolidone (PVP) polymer.
Amorphous form of the compound of Formula I
The spray-dried dispersion is characterized in that the compound of Formula I is present in an amorphous form.
HPMCAS polymer as the polymer
A spray-dried dispersion includes the compound of Formula I together with an HPMCAS polymer.
Compound-to-HPMCAS ratio range
The spray-dried dispersion is defined by a ratio of the compound of Formula I to the HPMCAS polymer of about 1:4 to about 4:1.
Specific HPMCAS subtype selection
The spray-dried dispersion is defined such that the HPMCAS polymer is selected from HPMCAS-MG, HPMCAS-LF, HPMCAS-LG, HPMCAS-MF, HPMCAS-HF, or HPMCAS-HG.
Using HPMCAS-MG
The spray-dried dispersion is characterized by using the HPMCAS-MG polymer as the HPMCAS polymer.
Overall claim coverage focuses on spray-dried dispersions of the compound of Formula I with defined polymer selections, particularly HPMCAS polymer, with additional coverage for an amorphous compound form and defined compound-to-polymer ratio ranges. Further narrowing is provided by selecting specific HPMCAS subtypes, including an embodiment using HPMCAS-MG.
Stated Advantages
Reduced TMD8 tumor xenograft growth in SCID mice with twice-daily oral dosing of Formula I.
Tolerability is reported in the in vivo tumor efficacy context.
Minimal fed/fasted effect for the spray-dried dispersion relative to the crystalline suspension, based on Cmax and AUC0-t summaries.
Treating or preventing BTK-associated cancers.
Treating or preventing autoimmune and inflammatory diseases.
Targeting subjects with BTK dysregulation and/or BTK inhibitor resistance.
Documented Applications
Treatment or prevention of BTK-associated cancers.
Treatment or prevention of autoimmune and inflammatory diseases.
Targeting subjects with BTK dysregulation and/or BTK inhibitor resistance, including monitoring using circulating tumor DNA.
In vivo evaluation of tumor efficacy using TMD8 tumor xenograft growth in SCID mice, with oral twice-daily dosing of Formula I.
Selecting and/or monitoring therapy with the compound of Formula I, including salts, amorphous form, polymorph form, and spray-dried dispersion.
Combination and switching strategies involving BTK inhibitors and other anticancer agents, with adjunct mention of CAR-T/immunotherapy.
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