Use of an erk inhibitor for the treatment of myelofibrosis

Patent metadata

Field	Value
Publication number	US-2024000777-A1
Application number	US-202118248124-A
Country	US
Kind code	A1
Filing date	Oct 7, 2021
Priority date	Oct 8, 2020
Publication date	Jan 4, 2024
Grant date	—

Abstract

The invention relates to the use of an ERK inhibitor in the treatment of myelofibrosis (MF). The invention also relates to a pharmaceutical combination comprising a) an ERK inhibitor and b) at least one further therapeutic agent, preferably ruxolitinib or a pharmaceutically acceptable salt thereof.

First claim

1 . A method of treating myeloproliferative neoplasm (MPN) in a patient, comprising administering an ERK1/2 inhibitor in combination with at least one further active agent to the patient, wherein the at least one further active agent is a JAK1/JAK2 inhibitor, a JAK2/FLT3 inhibitor, a JAK2 V617F inhibitor, a JAK2 inhibitor, JAK1 inhibitor or a JAK2/Src inhibitor.

2 . The method of claim 1 wherein the myeloproliferative neoplasm is selected from myelofibrosis (MF), essential thrombocythemia (ET), polycythemia vera (PV) and combinations thereof.

3 . The method of claim 2 , wherein the myelofibrosis comprises is primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (PET-MF) or post-polycythemia vera myelofibrosis (PPV-MF).

4 . The method of claim 3 , wherein said patient has thrombocytopenia associated with myelofibrosis.

5 . The method of claim 3 , wherein said patient has neutropenia associated with myelofibrosis.

6 . The method of claim 3 , wherein said patient has a peripheral blood platelet count of less than or equal to 50,000/μL before treatment.

7 . The method of claim 3 , wherein said patient has a peripheral blood platelet count of less than or equal to 75,000/μL before treatment.

8 . The method of claim 1 , wherein the myeloproliferative neoplasm (MPN) is primary myelofibrosis (PMF).

9 . The method of claim 1 wherein median survival time increases by at least 3 months after treatment.

10 . The method of claim 1 wherein said patient achieves an Hb improvement of ≥2.0 g/dL or ≥1.5 g/dL after treatment.

11 . The method of claim 1 any one of the claims 1 to 8 wherein said patient completely responds to the treatment.

12 . The method of claim 1 wherein the myeloproliferative neoplasm (MPN) is newly diagnosed MF.

13 . (canceled)

14 . (canceled)

15 . The method of claim 1 , wherein the at least one further active agent is ruxolitinib, or a pharmaceutically acceptable salt thereof.

16 . The method of claim 15 , wherein ruxolitinib or a pharmaceutically acceptable salt thereof, is administered at a total daily dose of 10 to 50 mg, administered once or twice daily.

17 . The method of claim 16 , wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily.

18 . The method of claim 1 , wherein the patient is receiving or has received prior therapy with ruxolitinib.

19 . The method of claim 18 wherein the prior therapy with ruxolitinib is administration at 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily.

20 . The method of claim 1 , wherein said ERK1/2 inhibitor is 4-(3-amino-6-((1 S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A), or pharmaceutical acceptable salt thereof.

21 . The method of claim 1 wherein Compound A is administered at a total daily dose of 100-300 mg, or 200-300 mg.

22 . The method of claim 1 wherein Compound A is administered at a total daily dose of 100 mg or 200 mg.

23 . A method of treating myeloproliferative neoplasm (MPN) in a patient, comprising administering Ruxolitinib, or a pharmaceutically acceptable salt therefore in combination with 4-(3-amino-6-((1 S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A), or a pharmaceutically acceptable salt thereof, to the patient.

24 . A pharmaceutical combination of 4-(3-amino-6-((1 S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide (Compound A), or a pharmaceutically acceptable salt thereof, and a JAK 1/2 inhibitor.

25 . A pharmaceutical combination according to claim 24 , wherein the JAK 1/2 inhibitor is ruxolitinib, or a pharmaceutically acceptable salt thereof.

26 . A method of treating myeloproliferative neoplasm (MPN) in a patient, comprising administering the pharmaceutical combination according to claim 24 to the patient.

Assignees

• Novartis Ag
• Univ Of Basel

Inventors

• Brkic Sime
• Menssen Hans
• Meyer Sara
• Radimerski Thomas
• Stivala Simona

Classifications

• A61K31/4965 Primary

  Non-condensed pyrazines · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06 Primary

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P35/02

  specific for leukemia · CPC title