JAK1 pathway inhibitors for the treatment of cytokine-related disorders
This disclosure relates to JAK1 pathway inhibitors and the use thereof in treating cytokine-related diseases or disorders such as cytokine release syndrome (CRS), hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), and CAR-T-cell-related encephalopathy syndrome (CRES).
1. A method for treating cytokine release syndrome in a subject, said method comprising administering to the subject one or more pharmaceutical compositions each comprising a JAK1 selective pathway inhibitor which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
2. The method of claim 1 , wherein the JAK1 selective pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.
3. The method of claim 1 , further comprising administering tocilizumab to said subject.
4. The method of claim 1 , further comprising administering a corticosteroid to said subject.
5. The method of claim 1 , further comprising administering prednisone to said subject.
6. The method of claim 1 , further comprising administering tocilizumab and a corticosteroid to said subject.
7. The method of claim 3 , wherein the JAK1 selective pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.
8. The method of claim 4 , wherein the JAK1 selective pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.
9. The method of claim 5 , wherein the JAK1 selective pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.
10. The method of claim 6 , wherein the JAK1 selective pathway inhibitor is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.
11. The method of claim 1 , wherein the method comprises administering to the subject a daily dose of from about 100 mg to 600 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the method comprises administering to the subject a daily dose of about 100 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the method comprises administering to the subject a daily dose of about 200 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
14. The method of claim 1 , wherein the method comprises administering to the subject a once-daily dose of about 200 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
15. The method of claim 1 , wherein the method comprises administering to the subject a daily dose of about 400 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
16. A method for treating cytokine release syndrome in a subject, said method comprising administering to the subject one or more pharmaceutical compositions each comprising a JAK1 selective pathway inhibitor which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers;
wherein the one or more pharmaceutical compositions are administered as one or more sustained release dosage forms each comprising the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof, and the one or more pharmaceutically acceptable carriers.
17. The method of claim 16 , wherein the method comprises administering to the subject a daily dose of from about 100 mg to 600 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
18. The method of claim 16 , wherein the method comprises administering to the subject a daily dose of about 100 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
19. The method of claim 16 , wherein the method comprises administering to the subject a daily dose of about 200 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
20. The method of claim 16 , wherein the method comprises administering to the subject a once-daily dose of about 200 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
21. The method of claim 16 , wherein the method comprises administering to the subject a daily dose of about 400 mg on a free base basis of the JAK1 selective pathway inhibitor, or a pharmaceutically acceptable salt thereof.
22. The method of claim 16 , wherein the one or more pharmaceutical compositions each comprise a JAK1 selective pathway inhibitor which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers selected from microcrystalline cellulose, a first hypromellose, a second hypromellose, lactose monohydrate, and magnesium stearate, or any combination thereof.
23. The method of claim 16 , wherein the one or more pharmaceutical compositions each comprise a JAK1 selective pathway inhibitor which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt, and one or more pharmaceutically acceptable carriers selected from microcrystalline cellulose, a first hypromellose, a second hypromellose, lactose monohydrate, and magnesium stearate, or any combination thereof.
24. The method of claim 16 , wherein the one or more pharmaceutical compositions each comprise a JAK1 selective pathway inhibitor which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, a first hypromellose, a second hypromellose, lactose monohydrate, and magnesium stearate.
25. The method of claim 16 , wherein the one or more pharmaceutical compositions each comprise a JAK1 selective pathway inhibitor which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt, microcrystalline cellulose, a first hypromellose, a second hypromellose, lactose monohydrate, and magnesium stearate.