Upadacitinib Maintenance for UC for ACG 2021

Upadacitinib was evaluated for maintenance therapy for ulcerative colitis in 451 participants, with striking efficacy vs placebo.

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1. Title of Presentation, Title Case Remo Panaccoine,1 Silvio Danese,2 Wen Zhou,11 Aileen Pangan,11 Xavier Hebuterne,3 Hiroshi Nakase,4 Geert D’Haens,5 Julian Panes,6 James O. Lindsay,7 Peter D. R. Higgins,8 Edward Loftus, Jr.,9 William Sandborn,10 Wangang Xie,11 Yuri Sanchez Gonzalez,11 Jianzhong Liu,11 Michael A. Weinreich,11 Severine Vermeire12 Efficacy and Safety of Upadacitinib Maintenance Therapy in Patients with Moderately to Severely Active Ulcerative Colitis: Results from a Randomized Phase 3 Study 1Division of Gastroenterology, University of Calgary, Calgary, Alberta, Canada; 2Humanitas University and Humanitas Research Hospital, IRCCS, Milan, Italy; 3Department of Gastroenterology and Clinical Nutrition, CHU de Nice, Université Côte d’Azur, Nice, France;4Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan; 5Department of Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, Netherlands; 6Hospital Clinic Barcelona, IDIPABS, CIBERehd, Barcelona, Spain; 7Department of Gastroenterology, The Royal London Hospital, Barts Health NHS Trust, London, UK; 8University of Michigan, Ann Arbor, Michigan, USA; 9Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA; 10Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA; 11AbbVie, Inc, North Chicago, IL, USA; 12Department of Gastroenterology & Hepatology, University Hospital Leuven, Leuven, Belgium # 64
2. • Ulcerative colitis (UC) is a chronic and progressive inflammatory bowel disease, where patients experience recurring symptoms of diarrhea, abdominal pain, and bowel urgency. • The Janus Kinase (JAK) family is composed of intracellular signalling proteins that regulate inflammatory signal transduction pathways and are involved in the pathogenesis of UC.3 - Upadacitinib (UPA) is an oral selective and reversible JAK inhibitor currently under investigation for the management of UC. • UPA demonstrated significantly greater efficacy as an induction therapy compared with placebo (PBO) in patients with moderately to severely active UC during two phase 3 induction trials (U-ACHIEVE Induction [NCT02819635] and U-ACCOMPLISH [NCT03653026]).4,5 The Need for a Targeted Ulcerative Colitis Maintenance Therapy 1.Kaur A, Goggolidou P. J Inflamm. 2020 Apr 21;17:15. 2.Monstad IL, et al. J Crohns Colitis. 2020 Dec 2:jjaa232. 3.Salas et al. Nature Reviews: Gastroenterology and Hepatology. 2020; 17: 323-337. 4.Danese S. et al. Efficacy and safety of upadacitinib induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the phase 3 U-ACHIEVE study. European Crohn’s and Colitis 2021 Congress. 5. Vermeire S. et al. Efficacy and safety of upadacitinib as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from phase 3 U- ACCOMPLISH study. European Crohn’s and Colitis 2021 Congress. OBJECTIVE: To evaluate the efficacy and safety of UPA 15 mg (UPA15) once daily (QD) and UPA30 (UPA30) mg QD compared to PBO as maintenance therapy for patients with moderately to severe UC who responded to UPA induction treatment.
3. 52 0 Week -5 2 4 8 U-ACHIEVE Maintenance Study Design Induction Studies (NCT02819635) (N = 278) Induction Study (NCT03653026) (N = 152) Primary endpoint: clinical remission Secondary Endpoints • Randomization into the maintenance study was stratified by previous biologic failure status, clinical remission during induction and corticosteroid use at week 0. U-ACHIEVE maintenance study (N=451; 52 wk) UPA 15 mg QD N=148 UPA 30 mg QD N=154 PBO QD N=149 Double blind; Randomization 1:1:1 8 wk - UPA 45 mg QD Clinical responders§ N = 451 § Clinical responders were defined as patients that successfully achieved clinical remission per Adapted Mayo score at the end of the 8-week induction period. QD, once daily; UPA, upadacitinib; CS, corticosteroid; wk, week Phase 2b M14-234 (N = 21)
4. Primary and Secondary Endpoint Definitions (all measured at week 52) Clinical Endpoint Definition Primary endpoint: clinical remission (Per Adapted Mayo Score) SFS ≤1 and not greater than baseline, RBS=0, and Mayo endoscopic subscore ≤1 Secondary endpoints Maintenance of clinical remission Clinical remission among patients that achieved clinical remission at the end of the induction therapy Corticosteroid-free clinical remission Clinical remission and corticosteroid-free for ≥90 days prior to wk 52 among patients with clinical remission at the end of the induction therapy Maintenance of clinical response Decrease from baseline of induction in Adapted Mayo score ≥ 2 points and ≥ 30%, PLUS a decrease in RBS ≥ 1 or an absolute RBS ≤ 1 among patients who achieved clinical response at the end of induction therapy Endoscopic improvement Endoscopic subscore ≤ 1 Maintenance of endoscopic improvement Endoscopic improvement among patients with endoscopic improvement at the end of the induction therapy Endoscopic remission Endoscopic subscore = 0 HEMI (Histologic-endoscopic mucosal improvement) Endoscopic subscore ≤ 1 and Geboes score ≤ 3.1
5. Baseline Demographics and Characteristics for U-ACHIEVE Maintenance Study Variable PBO (n=149) UPA 15 mg QD (n=148) UPA 30 mg QD (n=154) Female, n (%) 64 (43) 53 (36) 68 (44) Race, white, n (%) 93 (62) 97 (66) 101 (66) Age, median (range), y 40 (17-75) 40 (21-75) 41 (17-76) Disease duration, mean (SD), y 9 (8) 9 (8) 8 (8) Weight, mean (SD), kg 72 (18) 74 (21) 73 (21) Disease extent Left-sided 79 (53) 66 (45) 68 (44) Extensive/pancolitis 70 (47) 82 (55) 86 (56) Fecal calprotectin§, median (range), mg/kg 1991 (30-28800) 1718 (30-28800) 1465 (30-28800) hsCRP, median (range), mg/L 4 (0.20-105) 4 (0.20-83) 4 (0.2-107) Baseline aminosalicylates use, n (%) 99 (66) 99 (67) 106 (69) Baseline corticosteroid use, n (%) 60 (40) 55 (37) 57 (37) Biologic-IR, n (%) 81 (54) 71 (48) 73 (47) Number of prior biologics, ≤1 24 (30) 26 (37) 26 (36) Number of prior biologics, >1 57 (70) 45 (63) 47 (64) Non−biologic-IR, n (%) 68 (46) 77 (52) 81 (53) Prior anti-TNF use, n (%) 72 (48) 68 (46) 69 (45) Prior vedolizumab use, n (%) 42 (28) 33 (22) 37 (24) Baseline Adapted Mayo score, n (%) ≤7 87 (58) 89 (60) 88 (58) >7 62 (42) 59 (40) 64 (42) Mean (SD) 7 (1) 7 (1) 7 (1) Data was collected at week 0 of baseline among the randomized responders for U-ACHIEVE Maintenance Study. § Number of patients = PBO 127, UPA15 130, UPA30 129 PBO, placebo; QD, once daily; UPA, upadacitinib; hsCRP, high-sensitivity C reactive protein; IR, inadequate responder
6. Results are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19. Statistical significance is determined via the graphical multiple testing procedure controlling the overall type I error rate of all primary and key secondary endpoints at the 0.05 level. Error bars are ±95% CI. *** P-value < 0.001. UPA15 and UPA30 Achieve Significance Compared to PBO for Clinical Remission Primary Endpoint: Clinical remission at 52 wk 0 20 40 60 80 100 Percentage of Patients PBO UPA 15 mg QD UPA 30 mg QD Number of patients: 149 148 154 12% 42% 52% *** *** 0 20 40 60 80 100 Percentage of Patients Maintenance of clinical remission CS-free clinical remission Maintenance of clinical response 22% 59% 70% 22% 57% 68% 19% 63% 77% *** *** *** *** *** *** PBO UPA15 UPA30
7. UPA15 and UPA30 Achieve Clinical Remission and Response Results are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19. Statistical significance is determined via the graphical multiple testing procedure controlling the overall type I error rate of all primary and key secondary endpoints at the 0.05 level. Error bars are ±95% CI. *** P-value < 0.001. CS, Corticosteroid UPA15 and UPA30 Achieve Significance Compared to PBO for Maintenance of Clinical Remission, CS-free Clinical Remission and Maintenance of Clinical Response Secondary Endpoints (all at week 52) 0 20 40 60 80 100 Percentage of Patients Maintenance of clinical remission CS-free clinical remission Maintenance of clinical response Number of patients: 54 47 58 54 47 58 134 135 144 22% 59% 70% 22% 57% 68% 19% 63% 77% *** *** *** *** *** *** 0 20 40 60 80 100 Percentage of Patients Maintenance of clinical remission CS-free clinical remission Maintenance of clinical response Number of patients: 54 47 58 54 47 58 134 135 144 22% 59% 70% 22% 57% 68% 19% 63% 77% *** *** *** *** *** *** PBO UPA15 UPA30 A B C
8. Results are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19. Statistical significance is determined via the graphical multiple testing procedure controlling the overall type I error rate of all primary and key secondary endpoints at the 0.05 level. Error bars are ±95% CI. *** PBO vs UPA15 or UPA30 P-value < 0.001. HEMI, Histologic-endoscopic mucosal improvement UPA15 and UPA30 Achieve Significance Compared to PBO for Endoscopic and Histologic Endpoints 0 20 40 60 80 100 Percentage of Patients PBO UPA 15 mg QD UPA 30 mg QD Endoscopic improvement Maintenance of endoscopic improvement Endoscopic remission Number of Patients: 149 148 154 74 63 69 149 148 154 6% 24% 26% 15% 49% 62% 19% 62% 70% *** *** *** *** *** *** 0 20 40 60 80 100 Percentage of Patients HEMI 149 148 154 12% 35% 49% *** *** 0 20 40 60 80 100 Percentage of Patients Maintenance of clinical remission CS-free clinical remission Maintenance of clinical response Number of patients: 54 47 58 54 47 58 134 135 144 22% 59% 70% 22% 57% 68% 19% 63% 77% *** *** *** *** *** *** PBO UPA15 UPA30 A B C
9. Overall Safety Summary text Adverse Event PBO N=149 PY= 87.4 UPA 15 mg QD N=148 PY= 119.3 UPA 30 mg QD N=154 PY=135.1 % E/100 PY† % E/100 PY† % E/100 PY† Any AE 75.8 492.2 77.7 304.2 78.6 304.9 Severe AE 12.1 27.5 4.1 5.9 5.8 7.4 Serious AE 12.8 27.5 6.8 9.2 5.8 6.7 AE leading to discontinuation of study drug 11.4 20.6 4.1 5.9 6.5 7.4 Any AE possibly related to study drug 38.9 153.4 37.2 91.3 41.6 117.7 AE, Adverse event † Events per 100 patient-years § Includes treatment emergent and non-treatment emergent deaths • No deaths§ were reported in the study.
10. Safety Summary: Most Frequently Reported Adverse Events AE, reported by ≥5% of patients in any treatment group§ PBO N=149 PYS= 87.4 UPA 15 mg QD N=148 PYS=119.3 UPA 30 mg QD N=154 PYS=135.1 % E/100 PY† % E/100 PY† % E/100 PY† Nasopharyngitis 10.1 18.3 12.2 22.6 14.3 22.9 Elevation of creatine phosphokinase 2.0 3.4 6.1 7.5 8.4 11.1 UC Exacerbation 30.2 57.2 12.8 20.1 7.1 8.1 Upper respiratory tract infection 4.0 6.9 4.7 6.7 5.8 8.9 Arthralgia 10.1 17.2 6.1 7.5 3.2 4.4 AE, adverse event † Events per 100 patient-years § Listed in decreasing order among UPA 30 mg QD percentages
11. Adverse Events of Special Interest Adverse Event PBO N=149, (PYS =87.4) UPA 15 mg QD N=148, (PYS= 119.3) UPA 30 mg QD N=154, (PYS=135.1) % E/100 PY* % E/100 PY* % E/100 PY* Serious infection 4.0 6.9 3.4 4.2 2.6 3.0 Opportunistic infection excluding TB or herpes zoster 0 0 0.7 0.8 0 0 Herpes zoster 0 0 4.1 5.0 3.9 4.4 Any malignancy excluding NMSC 0.7 1.1 0.7 0.8 1.3 1.5 Any NMSC 0 0 0 0 1.3 1.5 Adjudicated VTE† 0 0 0 0 1.3 1.5 Adjudicated MACE‡ 0.7 1.1 0 0 0 0 Adjudicated gastrointestinal perforation 0.7 2.3 0 0 0 0 Anemia§ 6.0 12.6 4.7 5.9 1.9 2.2 Creatine phosphokinase elevation 2.0 3.4 6.1 7.5 8.4 11.1 Hepatic disorder 2.0 5.7 6.8 16.8 5.2 7.4 Neutropenia 1.3 2.3 2.7 4.2 5.8 8.9 Lymphopenia 1.3 3.4 2.0 2.5 1.9 3.0 * Events per 100 patient-years; † VTE defined as deep vein thrombosis and pulmonary embolism (fatal and non-fatal); ‡ Adjudicated MACE defined as cardiovascular death, non- fatal myocardial infarction, and non-fatal myocardial infarction stroke; § Based on CMQ search TB, tuberculosis; NMSC, non-melanoma skin cancer; MACE, major adverse cardiovascular event; VTE, venous thromboembolism
12. Both UPA15 and UPA30 were well-tolerated in patients with moderately to severely active UC. No new types of important safety risks were observed compared to the known safety profile of UPA. Higher rates of certain AESI were reported in UPA treatment arms. UPA30 demonstrated numerically greater clinical efficacy of approximately 10% compared to UPA15 for most endpoints. UPA15 and UPA30 had Significantly Greater Efficacy Compared to PBO for All Primary and Secondary Endpoints at Week 52 Based on Clinical, Endoscopic, and Histologic Evaluations