Combination therapy comprising btk inhibitor and belumosudil

HK40135205APending Publication Date: 2026-07-17KADMON CORP LLC
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Patent Information

Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
KADMON CORP LLC
Filing Date
2026-06-08
Publication Date
2026-07-17

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Abstract

Disclosed herein are methods of treating a disease selected from graft-versus-host disease (GVHD), systemic sclerosis (scleroderma), chronic lung allograft dysfunction (CLAD), restrictive allograft syndrome (RAS), and bronchiolitis obliterans syndrome (BOS) using a combination of a BTK inhibitor (such as rilzabrutinib) and belumosudil.
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Description

This article discloses a method for treating diseases selected from graft-versus-host disease (GVHD), systemic sclerosis (scleroderma), chronic lung allogeneic graft dysfunction (CLAD), restrictive allogeneic graft syndrome (RAS), and bronchiolitis obliterans syndrome (BOS) using combination therapy with BTK inhibitors such as rilzabrutinib and belumosudil. Abstract

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of treating a disease or disorder selected from systemic sclerosis and a transplant- associated dysfunction in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of a combination comprising: (a) a Bruton’s tyrosine kinase (BTK) inhibitor, and (b) 2-{3-[4-(lH-indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N- (propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof.

2. A method of treating a disease or disorder selected from graft-versus-host disease (GVHD), systemic sclerosis (scleroderma), chronic lung allograft dysfunction (CLAD), restrictive allograft syndrome (RAS), and bronchiolitis obliterans syndrome (BOS) in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of a combination comprising: (a) a Bruton’s tyrosine kinase (BTK) inhibitor, and (b) 2-{3-[4-(lH-indazol-5- ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof.

3. A method for treating graft-versus-host disease (GVHD) in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of a combination comprising: (a) a Bruton’s tyrosine kinase (BTK) inhibitor, and (b) 2-{3-[4-(lH-indazol-5- ylamino)-2-quinazolinyI]phenoxy}-N-(propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof.

4. A method for treating systemic sclerosis (scleroderma) in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of a combination comprising: (a) a Bruton’s tyrosine kinase (BTK) inhibitor, and (b) 2-{3-[4-(lH-indazol-5- ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof.

5. A method for treating chronic lung allograft dysfunction (CLAD) in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of a combination comprising: (a) a Bruton’s tyrosine kinase (BTK) inhibitor, and (b) 2-{3-[4-(lH- indazol-5-ylamino)-2-quinazolinyl]phenoxy)-N-(propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof.

6. A method for treating restrictive allograft syndrome (RAS) in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of a combination comprising: (a) a Bruton’s tyrosine kinase (BTK) inhibitor, and (b) 2-{3-[4-(1H- indazol-5-ylamino)-2-quinazolinyl]phenoxy)-N-(propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof.

7. A method for treating bronchiolitis obliterans syndrome (BOS) in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of a combination comprising: (a) a Bruton’s tyrosine kinase (BTK) inhibitor, and (b) 2-{3-[4-(lH- indazol-5-ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 1-7, wherein the BTK inhibitor is a reversible BTK inhibitor.

9. The method of any one of claims 1-7, wherein the BTK inhibitor is an irreversible BTK inhibitor.

10. The method of any one of claims 1-9, wherein the BTK inhibitor is (i) (R)-2-[3-[4-amino-3- (2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile or a pharmaceutically acceptable salt thereof; (ii) 1- [(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2- propen- 1 -one or a pharmaceutically acceptable salt thereof; or (iii) (4-amino-3-(4-phenoxyphenyl)- l-[(3R)-l-(prop-2-enoyl)piperidin-3-yl]-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein the BTK inhibitor is (R)-2-[3-[4-amino-3-(2-fluoro-4- phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3- yl)piperazin-l-yl]pent-2-enenitrile or a pharmaceutically acceptable salt thereof.

12. A method for treating graft-versus-host disease (GVHD) in a human patient in need thereof comprising administering to the human patient a therapeutically effective amount of a combination comprising: (a) (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l- yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile or apharmaceutically acceptable salt thereof, and (b) 2-{3-[4-(lH-indazol-5-ylamino)-2- quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide or a pharmaceutically acceptable salt thereof.

13. The method of any one of claims 2, 3, and 12, wherein GVHD is chronic GVHD (cGVHD).

14. The method of any one of claims 1-13, wherein 2-{3-[4-(lH-indazol-5-ylamino)-2- quinazolinyl]phenoxy }-N-(propan~2-yl) acetamide or a pharmaceutically acceptable salt thereof is administered to the human patient at a daily dosage of up to about 400 mg.

15. The method of claim 14, wherein 2-{3-[4-(lH-indazol-5-ylamino)-2- quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide, or a pharmaceutically acceptable salt thereof, is administered to the human patient at a daily dosage of about 50-400 mg.

16. The method of claim 14 or 15, wherein 2-{3-[4-(lH-indazol-5-ylamino)-2- quinazolinyl]phenoxy }-N-(propan-2-yl) acetamide, or a pharmaceutically acceptable salt thereof, is administered to the human patient at a dose of about 50 mg, 100 mg, 150 mg, or 200 mg.

17. The method of claim 16, wherein the dose is administered to the human patient once or twice daily.

18. The method of any one of claims 1-17, wherein 2-{3-[4-(lH-indazol-5-ylamino)-2- quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide, or a pharmaceutically acceptable salt thereof, is administered orally.

19. The method of any one of claims 10-18, wherein (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, is administered to the human patient at a daily dosage of up to about 800 mg.

20. The method of claim 19, wherein (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, is administered to the human patient at a daily dosage of about 50-800 mg.

21. The method of claim 19 or 20, wherein (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, is administered to the human patient at a dose of about 100 mg, 200 mg, or 400 mg.

22. The method of claim 21, wherein the dose of (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof is administered to the human patient once a day or twice a day.

23. The method of any one of claims 10-22, wherein the (E) isomer (R)-2-[3-[4-amino-3-(2- fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, is administered to the human patient.

24. The method of any one of claims 10-22, wherein the (Z) isomer (R)-2-[3-[4-amino-3-(2- fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4- (oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, is administered to the human patient.

25. The method of any one of claims 10-22, wherein a mixture of (E) and (Z) isomers of (R)-2- [3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l -carbonyl]- 4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, is administered to the human patient.

26. The method of any one of claims 10-25, wherein (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, is administered orally.

27. The method of any one of claims 10-26, wherein (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, and 2-{3-[4-(lH-indazol-5- ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide, or a pharmaceutically acceptable salt thereof, are administered separately.

28. The method of claim 27, wherein (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin-l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, and 2-{3-[4-(lEl-indazol-5- ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide, or a pharmaceutically acceptable salt thereof, are administered sequentially.

29. The method of any one of claims 10-28, wherein (R)-2-[3-[4-amino-3-(2-fluoro-4-phenoxy- phenyl)pyrazolo[3,4-d]pyrimidin-l-yl]piperidine-l-carbonyl]-4-methyl-4-[4-(oxetan-3-yl)piperazin- l-yl]pent-2-enenitrile, or a pharmaceutically acceptable salt thereof, and 2-{3-[4-(lH-indazol-5- ylamino)-2-quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide, or a pharmaceutically acceptable salt thereof, are administered simultaneously.