Use of inhibitors of bruton's tyrosine kinase (BTK)
Inventors
Buggy, Joseph J. • Fyfe, Gwen • Honigberg, Lee • Loury, David J.
Assignees
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Publication Number
US-10653696-B2
Publication Date
2020-05-19
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 treating mantle cell lymphoma in an individual with an inhibitor of Bruton's tyrosine kinase (Btk). The method comprises orally administering a 560 mg dose of the inhibitor of Btk on a continuous once-daily regimen until progression of the mantle cell lymphoma or unacceptable toxicity, while lymphocytosis is not considered progression. The method is configured so that the individual achieves a complete response.
The treatment approach is further characterized by pharmacokinetic and pharmacodynamic performance constraints. The administration is such that the individual achieves an AUC(0-24) greater than about 100 ng*h/ml, and more than 90% of the Btk active sites in peripheral blood mononuclear cells are occupied about 24 hours after dosing. In certain embodiments, the once-daily regimen is continued for at least 6 months.
The disclosure also includes extensive structural scope for kinase inhibitors using multiple chemical formulas, variable substituents, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable prodrugs, and pharmaceutically acceptable active metabolites. It further includes an irreversible kinase inhibitor concept in which the inhibitor moiety binds to kinase active sites, including a Btk kinase cysteine homolog.
Claims Coverage
The claim coverage centers on a mantle cell lymphoma treatment method using an orally administered 560 mg inhibitor of Bruton's tyrosine kinase on a continuous once-daily regimen, with lymphocytosis not counted as progression and a goal of complete response. Dependent features add pharmacokinetic exposure and target-occupancy thresholds, a minimum continuation duration, and a specified inhibitor structure.
Oral 560 mg continuous once-daily Btk inhibitor regimen for mantle cell lymphoma
Treating mantle cell lymphoma in an individual by orally administering a 560 mg dose of an inhibitor of Bruton's tyrosine kinase (Btk) on a continuous once-daily regimen until progression of the mantle cell lymphoma or unacceptable toxicity.
Lymphocytosis not considered progression
The method specifies that lymphocytosis is not considered progression of the mantle cell lymphoma.
Complete response as the treatment outcome
The method is wherein the individual achieves a complete response.
Btk inhibitor structure
The method is wherein the inhibitor of Btk has the structure shown in the claim.
Pharmacokinetic exposure threshold AUC(0-24) > about 100 ng*h/ml
The administration is such that the resulting AUC(0-24) is greater than about 100 ng*h/ml.
Target occupancy threshold in peripheral blood mononuclear cells at 24 hours
The method specifies that 24 hours after administration more than 90% of Btk active sites in peripheral blood mononuclear cells are occupied by the inhibitor.
Minimum treatment duration of at least 6 months
The method further includes continuing the once-daily regimen for at least 6 months.
Overall, the claim coverage focuses on mantle cell lymphoma treatment using an orally administered 560 mg inhibitor of Bruton's tyrosine kinase on a continuous once-daily regimen, with lymphocytosis not treated as progression and a requirement that the individual achieves a complete response. Dependent refinements provide an AUC(0-24) threshold, a >90% Btk active-site occupancy threshold in peripheral blood mononuclear cells at 24 hours, and a minimum continuation duration of at least 6 months.
Stated Advantages
Lymphocytosis is not considered progression of the mantle cell lymphoma.
Achievement of a complete response.
Tailors physical/biological properties including solubility, absorption, metabolism, PK, CYP interactions, drug-drug interactions, protein/lipid binding, and tissue distribution.
Uses an irreversible kinase inhibitor approach in which an inhibitor moiety binds to kinase active sites, including a Btk kinase cysteine homolog.
References tailoring chemical reactivity to address PK/toxicity and off-target effects.
Documented Applications
Treating mantle cell lymphoma in an individual, including an individual who has already received at least one prior therapy for mantle cell lymphoma.
Treating mantle cell lymphoma in a treatment-naive individual.
Treating multiple lymphoid malignancies including MALT lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, Waldenstrom macroglobulinemia, multiple myeloma, and leukemia by mobilizing malignant-associated cells with an orally administered irreversible Btk inhibitor and monitoring peripheral blood responses to guide initiation of a second cancer treatment regimen.
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