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Combination therapy for treatment of hematological diseases

A technology for blood diseases and leukemia, which is applied in the field of combination therapy for blood diseases, and can solve problems such as incurable diseases

Pending Publication Date: 2021-10-08
INCYTE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Current therapies for blood disorders such as multiple myeloma often do not cure the disease, and nearly all patients eventually become resistant to these therapies

Method used

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  • Combination therapy for treatment of hematological diseases
  • Combination therapy for treatment of hematological diseases
  • Combination therapy for treatment of hematological diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment A

[0166] Example A: In Vitro JAK Kinase Assay

[0167] Selective JAK1 inhibitors that can be used in combination with immunomodulators and steroids for the treatment of hematological diseases or disorders were tested for their inhibitory activity on JAK targets according to the following in vitro assay described in Park et al., Analytical Biochemistry 1999, 269, 94-104 . The catalytic domains of human JAK1 (a.a.837-1142), JAK2 (a.a.828-1132) and JAK3 (a.a.781-1124) with N-terminal His tags were expressed in insect cells using baculovirus and purified. The catalytic activity of JAK1, JAK2 or JAK3 was determined by measuring the phosphorylation of biotinylated peptides. Phosphorylated peptides were detected by homogeneous time-resolved fluorescence (HTRF). ICs of compounds were measured for each kinase in 40 μL reactions 50 , the reaction contained enzyme, ATP and 500 nM peptide in 50 mM Tris (pH 7.8) buffer with 100 mM NaCl, 5 mM DTT and 0.1 mg / mL (0.01%) BSA. For 1mM IC 50T...

Embodiment 1

[0168] Example 1: Clinical research on the treatment of multiple myeloma with JAK1 selective inhibitors

[0169] I. Design:

[0170] ·Single group

[0171] 2 stages

[0172] Triple combination: itatinib (compound 1, Table 1), steroid (methylprednisolone or dexamethasone), and lenalidomide

[0173] II. Main objectives:

[0174] • ORR (CR+VGPR+PR). ORR (Objective Response Rate) is defined as after each 4-week or 28-day treatment cycle, partial response (PR), very good Percentage of participants who responded (VGPR) or completely responded (CR).

[0175] III. Primary endpoint

[0176] ·IMWG standard tools

[0177] IV. Secondary endpoints:

[0178] · Overall survival (OS)

[0179] · Progression-free survival (PFR)

[0180] Time to Response (TTR): defined as the time from initiation of therapy to first sign of PR, VGPR, or CR

[0181] Duration of Response (DOR): Measured from when the responder starts responding to when the responder loses response

[0182] The safety a...

Embodiment 2

[0201] Example 2. In Vitro Analysis of the Viability of Multiple Myeloma Cell Lines by Itatinib, Lenalidomide, and Dexamethasone Combination Therapy

[0202] Human multiple myeloma cell lines KMS12BM, OPM2 (DSMZ), MM1.R, MM1.S (ATCC) and KMS11 (JCRB) were mixed in 100 μL medium with 10 4 Cells were seeded into white 96-well plates (Greiner Bio One). A combination of dexamethasone (Sigma), lenalidomide (Chemscene), itatinib or DMSO control was then added. Doses were chosen based on preliminary studies aimed at finding the sensitivity of each cell line to these agents. Each dose combination was performed in triplicate. After 72 hours, Cell Titer Glo (Promega) assay was performed according to the manufacturer's protocol to assess cell viability.

[0203] Such as Figure 1-Figure 5 As shown, none of the cell lines tested were sensitive to itatinib as a single agent as evidenced by no change in viability when compared to DMSO-treated controls. Each cell line has a different sen...

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Abstract

The present application relates to treatment of a hematological disease selected from leukemia, lymphoma, and multiple myeloma in a patient in need thereof, comprising administering to the patient: (a) a therapeutically effective amount of a selective JAK1 inhibitor; (b) a therapeutically effective amount of an immunomodulatory agent, and (c) a therapeutically effective amount of a steroid.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application Serial No. 62 / 753,409, filed October 31, 2018, the disclosure of which is incorporated herein by reference in its entirety. technical field [0003] The present application relates to the treatment of a blood disorder selected from leukemia, lymphoma and multiple myeloma in a patient in need thereof, comprising administering to the patient: (a) a therapeutically effective amount of a selective JAK1 inhibitor; (b) a therapeutically effective amount of an immune a modulator, and (c) a therapeutically effective amount of a steroid. Background technique [0004] The Janus kinase (JAK) / signal transducer and activator of transcription (STAT) pathway is considered a key player in hematopoiesis and immune response because of its role in cytokine receptors, a group of more than 30 receptors that recognize specific cytokines. A superfamily of transmembrane prot...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K31/519A61K31/4365A61K31/454A61K31/56A61P35/02A61K31/573A61K45/06
CPCA61K9/0019A61K31/519A61K31/454A61P35/02A61K31/573A61K45/06A61K31/4155A61K31/437A61K31/4035A61K2300/00A61K31/4015A61P35/00
Inventor A·阿萨德
Owner INCYTE CORP
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