Dosing regimens of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazinyl)-pyrimidin-5-yl)ethan-1-amine for treatment of indolent systemic mastocytosis
Inventors
Mar, Brenton • Boral, Anthony L. • Lin, Hui-Min • Shi, Hongliang
Assignees
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Publication Number
US-12252494-B2
Publication Date
2025-03-18
Expiration Date
Abstract
Crystalline Forms of Compound (I): pharmaceutically acceptable salts thereof and solvates of any of the foregoing are disclosed. Pharmaceutical compositions comprising the same, methods of treating disorders and conditions associated with oncogenic KIT and PDGFRA alterations using the same, and methods for making Compound (I) and crystalline forms thereof are also disclosed.
Core Innovation
The invention relates to a method of treating a patient with indolent systemic mastocytosis (ISM) by administering Compound (I) or a pharmaceutically acceptable salt of Compound (I). The dosage regimen described comprises administering 25 mg of Compound (I) once daily, or administering an amount equivalent to 25 mg of Compound (I) once daily for a pharmaceutically acceptable salt.
Compound (I) is associated with specific chemical forms including free base and pharmaceutically acceptable salts, with an example hydrochloride salt. The partial content further describes that Compound (I) is defined by Formula (I) with a variable substituent X1, including halogen or activated phenol substituents, and identifies representative members such as hydrochloride salt 3.5 HCl (2A).
In the context of the treatment method, dependent refinements specify patient selection based on KIT mutation details, and refinement based on symptom severity using an indolent systemic mastocytosis-symptom assessment form (ISM-SAF). Additional dependent features include co-administration of an antihistamine at an effective amount.
Claims Coverage
The independent claim covers administering Compound (I) or a pharmaceutically acceptable salt of Compound (I) to treat a patient with indolent systemic mastocytosis (ISM) using a once-daily regimen at a dose equivalent to 25 mg of Compound (I). The claim set includes dependent features that refine patient selection by KIT exon/mutation identity and symptom severity, and that optionally add antihistamine co-therapy.
Once-daily administration of 25 mg Compound (I) for ISM
A method of treating a patient with indolent systemic mastocytosis (ISM) comprising administering to the patient 25 mg of Compound (I) once daily, or administering a pharmaceutically acceptable salt of Compound (I) in an amount equivalent to 25 mg of Compound (I) once daily.
KIT Exon 17 mutation patient selection
The method wherein the patient has a mutation in Exon 17 in KIT.
KIT Exon 17 D816 mutation
The method wherein the patient has a D816 mutation in KIT in Exon 17.
KIT Exon 17 D816V mutation
The method wherein the D816 mutation is D816V.
ISM-SAF symptom severity threshold
The method wherein the patient has a minimum total symptom score (TSS) exceeding 28, as assessed using the indolent systemic mastocytosis-symptom assessment form (ISM-SAF).
Antihistamine co-administration
The method further includes administering an effective amount of an antihistamine.
Across the claims, the core coverage is a treating method for indolent systemic mastocytosis (ISM) based on once-daily administration of Compound (I) at a 25 mg dose equivalent, with dependent refinements specifying KIT mutation criteria including Exon 17 and D816V, an ISM-SAF symptom threshold, and optional antihistamine co-therapy.
Stated Advantages
Improves ISM-SAF total symptom score and symptom domains at 16 weeks.
Similar efficacy to higher doses.
Favorable tolerability and safety.
Manufacturability advantages including stability and reduced impurities versus prior SFC enantiomer separation.
Improved formulation properties.
Improved enantiomeric excess and yields.
Documented Applications
Treating a patient with indolent systemic mastocytosis (ISM) using Compound I administered at 25 mg once daily, or a pharmaceutically acceptable salt equivalent to 25 mg once daily.
Treating ISM patients selected based on KIT exon 17 mutation status, including KIT exon 17 mutations such as D816/D816V and D816V, and using an ISM-SAF minimum total symptom score exceeding 28.
Treating ISM with co-administration of an antihistamine at an effective amount.
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