Use of inhibitors of Brutons tyrosine kinase (Btk)
Inventors
Assignees
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Publication Number
US-11672803-B2
Publication Date
2023-06-13
Expiration Date
Abstract
Disclosed herein are methods for treating a cancer comprising: a. administering a Btk inhibitor to a subject sufficient to result in an increase or appearance in the blood of a subpopulation of lymphocytes defined by immunophenotyping; b. determining the expression profile of one or more biomarkers from one or more subpopulation of lymphocytes; and c. administering a second agent based on the determined expression profile.
Core Innovation
The invention relates to a method for treating chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) by orally administering a therapeutically effective amount of an irreversible inhibitor of Bruton's tyrosine kinase (Btk) on a continuous daily regimen until progression of the CLL or SLL or unacceptable toxicity. In the method, lymphocytosis is not considered progression of the CLL or SLL. The irreversible inhibitor forms a covalent bond with Cys481 of Bruton's tyrosine kinase.
The irreversible inhibitor of Btk is a small organic molecule having a structure in which Z′ is an optionally substituted fused heterocyclic ring system comprising from 2-4 nitrogen heteroatoms. The optionally substituted fused heterocyclic ring system consists of a 5-membered ring comprising at least one nitrogen heteroatom fused to a 6-membered ring comprising at least one nitrogen heteroatom.
The therapeutically effective amount results in greater than 90% of the Btk active sites in peripheral blood mononuclear cells being occupied by the irreversible inhibitor of Btk twenty-four hours following administration. The disclosed method uses pharmacodynamic occupancy as a defining parameter for the therapeutically effective amount.
Claims Coverage
The independent claims center on continuous daily oral treatment of CLL or SLL with an irreversible Btk inhibitor. The inventive features include covalent Cys481 binding, a fused heterocyclic ring system with 2-4 nitrogen heteroatoms, lymphocytosis not counted as progression, and a pharmacodynamic occupancy threshold in peripheral blood mononuclear cells at 24 hours.
Oral continuous daily irreversible Btk inhibition for CLL or SLL with lymphocytosis not counted as progression
Orally administering to an individual a therapeutically effective amount of an irreversible inhibitor of Bruton's tyrosine kinase (Btk) on a continuous daily regimen until progression of the CLL or SLL or unacceptable toxicity, wherein lymphocytosis is not considered progression of the CLL or SLL.
Covalent Cys481 binding by a small organic irreversible Btk inhibitor defined by a fused heterocyclic ring system
The irreversible inhibitor of Btk is a small organic molecule having a structure in which Z′ is an optionally substituted fused heterocyclic ring system comprising from 2-4 nitrogen heteroatoms, the fused system consists of a 5-membered ring comprising at least one nitrogen heteroatom fused to a 6-membered ring comprising at least one nitrogen heteroatom, and the irreversible inhibitor forms a covalent bond with Cys481 of Bruton's tyrosine kinase.
Pharmacodynamic definition of therapeutically effective amount by >90% Btk active site occupancy at 24 hours
The administration results in more than 90% of the Btk active sites in the peripheral blood mononuclear cells of the individual being occupied by the irreversible inhibitor of Btk twenty-four hours following said administration.
The independent-claim coverage is centered on an orally administered continuous daily regimen using an irreversible small-molecule Btk inhibitor that covalently bonds Cys481, with the inhibitor defined by an optionally substituted fused heterocyclic ring system containing 2-4 nitrogen heteroatoms, and a pharmacodynamic requirement of >90% Btk active-site occupancy in peripheral blood mononuclear cells at 24 hours while lymphocytosis is not treated as progression.
Stated Advantages
Lymphocytosis is not considered progression of the CLL or SLL.
Achieves a defined pharmacodynamic effect with >90% BTK active-site occupancy in peripheral blood mononuclear cells 24 hours following administration.
Documented Applications
Treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in an individual using an orally administered irreversible Btk inhibitor on a continuous daily regimen.
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