mTOR/JAK INHIBITOR COMBINATION THERAPY

• US 20120214825A1
• Filed: 02/17/2012
• Published: 08/23/2012
• Est. Priority Date: 02/18/2011
• Status: Active Grant

• Current Assignee: Incyte Corporation, Novartis Pharma AG (Novartis Ag)
• Original Assignee: Incyte Corporation, Novartis Pharma AG (Novartis Ag)
• Inventors: Vannucchi, Alessandro M., Bogani, Costanza, Guglielmelli, Paola
• Granted Patent: US 9,993,480 B2
• Time in Patent Office: Days
• US Class Current: 514/262.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/436 the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid

Abstract

Provided herein is a combination therapy comprising an mTOR inhibitor and a JAK inhibitor. The combination therapy is useful for the treatment of a variety of cancers, including MPNs. The combination therapy is also useful for the treatment of any number of JAK-associated diseases.

Claims

1. A method of treating cancer in a subject in need thereof, comprising administering to the subject an mTOR inhibitor and a compound of formula I:

2. The method of claim 1, wherein the compound of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

3. The method of claim 1, wherein the mTOR inhibitor is Everolimus (RAD001) or 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol (PP242).

4. The method of claim 1, wherein the mTOR inhibitor and compound of formula I are in a single formulation or unit dosage form.

5. The method of claim 4, further comprising a pharmaceutically acceptable carrier.

6. The method of claim 1, wherein the mTOR inhibitor and compound of formula I are administered separately.

7. The method of claim 1, wherein the cancer is a myeloproliferative neoplasm.

8. The method of claim 7, wherein the myeloproliferative neoplasm is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary or idiopathic myelofibrosis (PMF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, and atypical chronic myelogenous leukemia.

9. The method of claim 7, wherein the myeloproliferative neoplasm is primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis

10. The method of claim 6, wherein the subject is human.

11. The method of claim 6, wherein the treatment comprises administering the mTOR inhibitor and compound of formula I at substantially the same time.

12. The method of claim 6, wherein the treatment comprises administering the mTOR inhibitor and compound of formula I at different times.

13. The method of claim 12, wherein the mTOR inhibitor is administered to the subject, followed by administration of a compound of formula I.

14. The method of claim 12, wherein the compound of formula I is administered to the subject, followed by administration of the mTOR inhibitor.

15. The method of claim 6, wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are in a single formulation or unit dosage form.

16. The method of claim 6, wherein the mTOR inhibitor and (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof, are in separate formulations or unit dosage forms.

17. The method of claim 6, wherein the mTOR inhibitor and/or compound of formula I are administered at dosages that would not be effective when one or both of the mTOR inhibitor and compound of formula I are administered alone, but which amounts are effective in combination.

18. A method of inhibiting STAT5 phosphorylation, comprising administering an mTOR inhibitor and a compound of formula I.

19. The method of claim 18, wherein the composition is administered to a subject in need thereof.

20. The method of claim 19, wherein the administration of the formulation treats a myeloproliferative neoplasm in the subject.

21. The method of claim 20, wherein the myeloproliferative neoplasm is selected from the group consisting of chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary or idiopathic myelofibrosis (PMF), chronic neutrophilic leukemia, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, and atypical chronic myelogenous leukemia.

22. The method of claim 20, wherein the myeloproliferative neoplasm is primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis

23-24. -24. (canceled)

25. A composition comprising an mTOR inhibitor and a compound of formula I:

26. The composition of claim 25, wherein the compound of formula I is (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile, or a pharmaceutically acceptable salt thereof.

27. The composition of claim 25, wherein the mTOR inhibitor is Everolimus (RAD001) or 2-(4-Amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol (PP242).

28. The composition of claim 25, further comprising a pharmaceutically acceptable carrier.

29. A method of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of the composition of claim 25.

30. The method of claim 29, wherein the cancer is a myeloproliferative neoplasm.