JP-7856429-B2 - Treatment methods for myeloproliferative disorders

Inventors

• ティマラ・ベリー
• ジョン・フッド
• カトリオナ・ジェイミーソン
• カーティス・エル・スクリブナー

Assignees

• インパクト バイオメディシンズ インコーポレイテッド

Dates

Publication Date

20260511

Application Date

20190924

Priority Date

20180925

Claims (16)

1. Compound I Alternatively, a pharmaceutical composition for use in a method for treating myeloproliferative disorders, comprising a pharmaceutically acceptable salt or hydrate thereof as an active ingredient, wherein the method is (i) Administer the compound or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient to a patient in need of treatment. (ii) The patient's thiamine level is monitored, and then (iii) if the thiamine level is lower than a reference value, the patient is administered thiamine or a thiamine equivalent, wherein the reference value is approximately 74 to approximately 222 nM/L of whole blood, where, Thiamine will be administered according to the following schedule: Take approximately 500 mg for 2 or 3 days, TID. For 3 to 5 days, take approximately 250 mg to 500 mg daily (QD), and Approximately 100 mg for 90 days, QD It is administered according to the following: Alternatively, thiamine equivalents are available according to the following schedule: Take approximately 500 mg for 2 or 3 days, TID. For 3 to 5 days, take approximately 250 mg to 500 mg daily (QD), and Approximately 100 mg for 90 days, QD The pharmaceutical composition is administered in such a manner that it is sufficient to deliver an amount of thiamine according to [a certain condition].
2. The pharmaceutical composition according to claim 1, wherein the patient's thiamine level is evaluated by analyzing one or more biomarkers related to thiamine deficiency.
3. The pharmaceutical composition according to claim 1, wherein thiamine is administered intravenously.
4. The pharmaceutical composition according to claim 1, wherein the thiamine equivalent is administered orally.
5. Furthermore, the pharmaceutical composition according to claim 1, comprising increasing the magnesium level of the patient.
6. The pharmaceutical composition according to claim 1, wherein the patient suffers from a myeloproliferative disorder.
7. The pharmaceutical composition according to claim 6 , wherein the myeloproliferative disorder is myelofibrosis.
8. The pharmaceutical composition according to claim 7 , wherein the myelofibrosis is primary myelofibrosis.
9. The pharmaceutical composition according to claim 8 , wherein the primary myelofibrosis is selected from intermediate-risk primary myelofibrosis and high-risk primary myelofibrosis.
10. The pharmaceutical composition according to claim 7 , wherein the myelofibrosis is secondary myelofibrosis.
11. The pharmaceutical composition according to claim 7 , wherein the myelofibrosis is post-essential thrombocythemia myelofibrosis.
12. The pharmaceutical composition according to claim 7 , wherein the myelofibrosis is post-polycythemia vera myelofibrosis.
13. The pharmaceutical composition according to claim 1, wherein the myeloproliferative disorder is acute myeloid leukemia (AML).
14. The pharmaceutical composition according to claim 1, wherein the myeloproliferative disorder is polycythemia vera.
15. The pharmaceutical composition according to claim 1, wherein the myeloproliferative disorder is essential thrombocythemia.
16. The pharmaceutical composition according to claim 1, wherein compound I is in the form of a dihydrochloride monohydrate.

Description

Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62/736,369 filed on 25 September 2018 and U.S. Provisional Application No. 62/783,076 filed on 20 December 2018, both of which are incorporated herein by reference. This invention provides a method for treating, stabilizing, or reducing the severity or progression of myeloproliferative disorders. The search for new therapeutic drugs has been significantly accelerated in recent years by a deeper understanding of the structures of disease-related enzymes and other biomolecules. One important class of enzymes that has been the subject of extensive research is protein kinases. Protein kinases constitute a vast family of structurally related enzymes that regulate various intracellular signaling processes. Because their structure and catalytic function are conserved, protein kinases are thought to have evolved from a common ancestral gene. Almost all kinases possess a similar 250-300 amino acid catalytic domain. Kinases can be classified into several families based on the substrates they phosphorylate (e.g., protein tyrosine, protein serine/threonine, lipids, etc.). Generally, protein kinases mediate intracellular signaling by inducing phosphoryl transfer from nucleoside triphosphates to protein acceptors involved in signaling pathways. These phosphorylation events act as molecular on/off switches capable of regulating or controlling the biological function of target proteins. These phosphorylation events are ultimately triggered in response to various extracellular and other stimuli. Examples of such stimuli include environmental and chemical stress signals (e.g., osmotic shock, heat shock, ultraviolet irradiation, bacterial endotoxins, and H₂O₂ ), cytokines (e.g., interleukin- 1 (IL-1) and tumor necrosis factor α (TNF-α)), and growth factors (e.g., granulocyte-macrophage colony-stimulating factor (GM-CSF) and fibroblast growth factor (FGF)). Extracellular stimuli can affect one or more cellular responses related to cell proliferation, migration, differentiation, hormone secretion, transcription factor activation, muscle contraction, glucose metabolism, protein synthesis regulation, and cell cycle regulation. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events, as described above. These diseases include, but are not limited to, autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease, and hormone-related disorders. Therefore, the discovery of useful protein kinase inhibitors as therapeutic agents remains crucial. This disclosure provides methods for treating, stabilizing, or reducing the severity or progression of one or more myeloproliferative disorders. In certain embodiments, the methods provided include mitigating one or more adverse events associated with the treatment of myeloproliferative disorders. In some such embodiments, one or more adverse events are thiamine deficiency. Depending on the embodiment, this disclosure provides a method for treating, stabilizing, or reducing the severity or progression of one or more myeloproliferative disorders, wherein the patient is given a compound of formula I: Alternatively, the method includes administering a pharmaceutically acceptable composition comprising a pharmaceutically acceptable salt or hydrate thereof. The compound of formula I is also referred to herein as "compound I." In some embodiments, compound I is in the dihydrochloride form. Compound I or a pharmaceutically acceptable salt thereof may also exist in hydrate form. In some such embodiments, compound I is in the dihydrochloride monohydrate form. Therefore, in some embodiments, the method provided includes administering compound II to a patient requiring compound II: Depending on the embodiment, this disclosure provides a treatment for myeloproliferative disorders, and the method is as follows: (i) administering compound I or a pharmaceutically acceptable salt or hydrate thereof (e.g., compound II) to patients in need of treatment, and (ii) monitoring the patient's thiamine levels. If thiamine levels are lower than the normal range, adjust the patient's thiamine levels. Includes. In some embodiments, the patient's thiamine level is adjusted if it is approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or more below the reference value. In some embodiments, the reference value is the patient's baseline thiamine level before administration of compound I. In some embodiments, the reference value is a thiamine level of approximately 74 nM/L to approximately 222 nM/L in whole blood. Depending on the embodiment, patients may be at risk of developing Wernicke encephalopathy. In some embodiments, a patient's thiamine levels are assessed by analyzing one or more biomarkers related to thiamine deficienc