Methods of treating crohn's disease and ulcerative colitis

Abstract

The present disclosure is directed to methods for treating Crohn's disease, and in particular, to methods for inducing clinical remission and/or endoscopic improvement of Crohn's disease, using a JAK1 inhibitor. In certain embodiments, the patient is administered an induction dose of the JAK1 inhibitor to induce clinical remission and/or endoscopic improvement of the Crohn's disease, followed by administration of at least one maintenance dose of the JAK1 inhibitor thereafter. In other embodiments, the present disclosure is directed to methods for treating ulcerative colitis using a JAK1 inhibitor.

1 - 103 . (canceled) 
     
     
         104 . A method of achieving clinical remission of moderately to severely active Crohn's disease in an adult patient, the method comprising:
 (i) orally administering to the patient once a day for at least 12 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and then   (ii) orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;   whereby the patient achieves clinical remission, and wherein clinical remission is an average daily liquid/very soft stool frequency of ≤2.8 and not greater than baseline, and an average daily abdominal pain of ≤1.0 and not greater than baseline.   
     
     
         105 . A method of achieving clinical remission of moderately to severely active Crohn's disease in an adult patient, the method comprising orally administering to the patient once a day for at least 12 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
 whereby the patient achieves clinical remission, and wherein clinical remission is an average daily liquid/very soft stool frequency of ≤2.8 and not greater than baseline, and an average daily abdominal pain of ≤1.0 and not greater than baseline.   
     
     
         106 . The method of  claim 105 , further comprising maintaining clinical remission of moderately to severely active Crohn's disease in the adult patient, the method comprising orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains clinical remission for the at least 36 weeks. 
     
     
         107 . The method of  claim 105 , further comprising maintaining clinical remission of moderately to severely active Crohn's disease in the adult patient, the method comprising orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains clinical remission for the at least 36 weeks. 
     
     
         108 . A method of achieving clinical remission of moderately to severely active ulcerative colitis in an adult patient, the method comprising:
 (i) orally administering to the patient once a day for at least 8 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and then   (ii) orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;   whereby the patient achieves clinical remission, and wherein clinical remission is a stool frequency subscore of ≤1, a rectal bleeding subscore of 0, and an endoscopic subscore of ≤1.   
     
     
         109 . A method of achieving clinical remission of moderately to severely active ulcerative colitis in an adult patient, the method comprising orally administering to the patient once a day for at least 8 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
 whereby the patient achieves clinical remission, and wherein clinical remission is a stool frequency subscore of ≤1, a rectal bleeding subscore of 0, and an endoscopic subscore of ≤1.   
     
     
         110 . The method of  claim 109 , further comprising maintaining clinical remission of moderately to severely active ulcerative colitis in the adult patient, the method comprising orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains clinical remission for the at least 44 weeks. 
     
     
         111 . The method of  claim 109 , further comprising maintaining clinical remission of moderately to severely active ulcerative colitis in the adult patient, the method comprising orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains clinical remission for the at least 44 weeks. 
     
     
         112 . A method of achieving clinical response of moderately to severely active Crohn's disease in an adult patient, the method comprising:
 (i) orally administering to the patient once a day for at least 12 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and then   (ii) orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;   whereby the patient achieves clinical response, and wherein clinical response is (i) an average daily liquid/very soft stool frequency score of ≥30% decrease from baseline and an average daily abdominal pain score reduction of not greater than baseline, or (ii) an average daily abdominal pain score ≥30% decrease from baseline and an average daily liquid/very soft stool frequency score of not greater than baseline.   
     
     
         113 . The method of  claim 112 , whereby the patient achieves an enhanced clinical response, and wherein an enhanced clinical response is a ≥60% decrease in an average daily liquid/very soft stool frequency and/or ≥35% decrease in the average daily abdominal pain score, and wherein both the average daily liquid/very soft stool frequency and the average daily abdominal pain score are not greater than baseline. 
     
     
         114 . A method of achieving clinical response of moderately to severely active Crohn's disease in an adult patient, the method comprising orally administering to the patient once a day for at least 12 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
 whereby the patient achieves clinical response, and wherein clinical response is (i) an average daily liquid/very soft stool frequency score of ≥30% decrease from baseline and an average daily abdominal pain score reduction of not greater than baseline, or (ii) an average daily abdominal pain score ≥30% decrease from baseline and an average daily liquid/very soft stool frequency score of not greater than baseline.   
     
     
         115 . The method of  claim 114 , further comprising maintaining clinical response of moderately to severely active Crohn's disease in the adult patient, the method comprising orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains clinical response for the at least 36 weeks. 
     
     
         116 . The method of  claim 114 , further comprising maintaining clinical response of moderately to severely active Crohn's disease in the adult patient, the method comprising orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains clinical response for the at least 36 weeks. 
     
     
         117 . A method of achieving clinical response of moderately to severely active ulcerative colitis in an adult patient, the method comprising:
 (i) orally administering to the patient once a day for at least 8 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and then   (ii) orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;   whereby the patient achieves clinical response, and wherein clinical response is a decrease from baseline in the Adapted Mayo score of ≥2 points and ≥30% decrease from baseline accompanied by (i) a decrease in rectal bleeding subscore of ≥1 or (ii) an absolute rectal bleeding subscore of ≤1.   
     
     
         118 . A method of achieving clinical response of moderately to severely active ulcerative colitis in an adult patient, the method comprising orally administering to the patient once a day for at least 8 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
 whereby the patient achieves clinical response, and wherein clinical response is a decrease from baseline in the Adapted Mayo score of ≥2 points and ≥30% decrease from baseline accompanied by (i) a decrease in rectal bleeding subscore of ≥1 or (ii) an absolute rectal bleeding subscore of ≤1.   
     
     
         119 . The method of  claim 118 , further comprising maintaining clinical response of moderately to severely active ulcerative colitis in the adult patient, the method comprising orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains clinical response for the at least 44 weeks. 
     
     
         120 . The method of  claim 118 , further comprising maintaining clinical response of moderately to severely active ulcerative colitis in the adult patient, the method comprising orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains clinical response for the at least 44 weeks. 
     
     
         121 . A method of achieving endoscopic remission of moderately to severely active Crohn's disease in an adult patient, the method comprising:
 (i) orally administering to the patient once a day for at least 12 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and then   (ii) orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;   whereby the patient achieves endoscopic remission, and wherein endoscopic remission is a Simplified Endoscopic Score for Crohn's disease (SES-CD) score of ≤4 and at least a two point reduction in the SES-CD score versus baseline, and no subscore >1 in any variable used to calculate the SES-CD score selected from the group consisting of size of ulcers, ulcerated surface, affected surface, and presence of narrowing.   
     
     
         122 . A method of achieving endoscopic remission of moderately to severely active Crohn's disease in an adult patient, the method comprising orally administering to the patient once a day for at least 12 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
 whereby the patient achieves endoscopic remission, and wherein endoscopic remission is a Simplified Endoscopic Score for Crohn's disease (SES-CD) score of ≤4 and at least a two point reduction in the SES-CD score versus baseline, and no subscore >1 in any variable used to calculate the SES-CD score selected from the group consisting of size of ulcers, ulcerated surface, affected surface, and presence of narrowing.   
     
     
         123 . The method of  claim 122 , further comprising maintaining endoscopic remission of moderately to severely active Crohn's disease in the adult patient, the method comprising orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains endoscopic remission for the at least 36 weeks. 
     
     
         124 . The method of  claim 122 , further comprising maintaining endoscopic remission of moderately to severely active Crohn's disease in the adult patient, the method comprising orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains endoscopic remission for the at least 36 weeks. 
     
     
         125 . A method of achieving endoscopic remission of moderately to severely active ulcerative colitis in an adult patient, the method comprising:
 (i) orally administering to the patient once a day for at least 8 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and then   (ii) orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;   whereby the patient achieves endoscopic remission, and wherein endoscopic remission is an endoscopic subscore of 0.   
     
     
         126 . A method of achieving endoscopic remission of moderately to severely active ulcerative colitis in an adult patient, the method comprising orally administering to the patient once a day for at least 8 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
 whereby the patient achieves endoscopic remission, and wherein endoscopic remission is an endoscopic subscore of 0.   
     
     
         127 . The method of  claim 126 , further comprising maintaining endoscopic remission of moderately to severely active ulcerative colitis in the adult patient, the method comprising orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains endoscopic remission for the at least 44 weeks. 
     
     
         128 . The method of  claim 126 , further comprising maintaining endoscopic remission of moderately to severely active ulcerative colitis in the adult patient, the method comprising orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains endoscopic remission for the at least 44 weeks. 
     
     
         129 . A method of achieving endoscopic response of moderately to severely active Crohn's disease in an adult patient, the method comprising:
 (i) orally administering to the patient once a day for at least 12 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and then   (ii) orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;   whereby the patient achieves endoscopic response, and wherein endoscopic response is (i) a decrease of >50% in the Simplified Endoscopic Score for Crohn's disease (SES-CD) score from baseline, or (ii) for subjects with an SES-CD score of 4 at baseline, at least a 2 point reduction.   
     
     
         130 . A method of achieving endoscopic response of moderately to severely active Crohn's disease in an adult patient, the method comprising orally administering to the patient once a day for at least 12 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
 whereby the patient achieves endoscopic response, and wherein endoscopic response is (i) a decrease of >50% in the Simplified Endoscopic Score for Crohn's disease (SES-CD) score from baseline, or (ii) for subjects with an SES-CD score of 4 at baseline, at least a 2 point reduction.   
     
     
         131 . The method of  claim 130 , further comprising maintaining endoscopic response of moderately to severely active Crohn's disease in the adult patient, the method comprising orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains endoscopic response for the at least 36 weeks. 
     
     
         132 . The method of  claim 130 , further comprising maintaining endoscopic response of moderately to severely active Crohn's disease in the adult patient, the method comprising orally administering to the patient once a day for at least 36 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains endoscopic response for the at least 36 weeks. 
     
     
         133 . A method of achieving endoscopic improvement of moderately to severely active ulcerative colitis in an adult patient, the method comprising:
 (i) orally administering to the patient once a day for at least 8 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent; and then   (ii) orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;   whereby the patient achieves endoscopic improvement, and wherein endoscopic improvement is an endoscopic subscore of ≤1.   
     
     
         134 . A method of achieving endoscopic improvement of moderately to severely active ulcerative colitis in an adult patient, the method comprising orally administering to the patient once a day for at least 8 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 45 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent;
 whereby the patient achieves endoscopic improvement, and wherein endoscopic improvement is an endoscopic subscore of ≤1.   
     
     
         135 . The method of  claim 134 , further comprising maintaining endoscopic improvement of moderately to severely active ulcerative colitis in the adult patient, the method comprising orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 15 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains endoscopic improvement for the at least 44 weeks. 
     
     
         136 . The method of  claim 134 , further comprising maintaining endoscopic improvement of moderately to severely active ulcerative colitis in the adult patient, the method comprising orally administering to the patient once a day for at least 44 weeks (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver 30 mg of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the patient maintains endoscopic improvement for the at least 44 weeks. 
     
     
         137 . The method of  claim 104 , comprising administering (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide as Freebase Hydrate Form C.