Australian multicenter real-world experience of upadacitinib induction therapy for moderate to severe ulcerative colitis

Background and Aim: Upadacitinib is a novel selective Janus kinase(JAK) inhibitor, with proven efficacy for ulcerative colitis (UC) in a clinical trial setting. It was not available on the Australian Pharmaceutical Benefits Scheme until May 2023 but received Therapeutic Goods Administration approval and became available to Australian patients via a product familiarization program (PFP) from September 2022. This study aimed to examine the outcomes of patients treated with upadacitinib for moderate to severe UC in an Australian real-world population. Methods: We conducted a retrospective multicenter study of adult patients with moderate to severe UC who commenced upadacitinib through the PFP from September 2022 to February 2023. Demographic and clinical data were collected at defined time points of baseline, Week 8, and Week 16 after induction. The primary outcome was clinical remission and response using patient-reported outcome (PRO2) definitions (STRIDE II guide-lines). Secondary endpoints included corticosteroid-free clinical remission(CFCR), biochemical response (defined as a normalization of C-reactive protein [CRP] level≤5 mg/dL and a fecal calprotectin [FCP] level≤150μg/g), and transmural remission assessed by intestinal ultrasound(IUS) (defined as bowel wall thickness [BWT]<3 mm with no Doppler activity). We also recorded adverse events. Results: A total of 720 patients were enrolled in the upadacitinib PFP, of whom 157 (34%) received a 16-week extended induction, and 155 (22%)were naive to advanced drug therapy (ADT). Detailed data were collected from 12 Australian centers for 129 patients participating in the PFP (40%female; median age, 38 years [range, 18–69]). Most patients (114, 88%)were previously exposed to ADT (anti-tumor necrosis factor therapy,101; vedolizumab, 78; tofacitinib, 42; 66% failed more than one drug class). Complete clinical data were available for all 129 patients at baseline and Week 8 and for 44 patients at Week 16. The rate of clinical remission was 23% at baseline, 82% at Week 8, and 93% at Week 16 (Table 1). In those with active disease at baseline, clinical response was achieved in77% at Week 8 and 94% at Week 16. There was no statistically significant difference in rate of clinical remission or response when stratified by prior biologic exposure. The rate of corticosteroid use at baseline was 40%,which decreased to 11% by Week 8 and 3% by Week 16. The rate of CFCR was 18% at baseline, 76% at Week 8, and 84% at Week 16. Rectal bleeding was present in 65% at baseline, with complete resolution of rectal bleeding seen in 77% at Week 8 and 92% by Week 16. Increased stool frequency was present in 94% at baseline, with normalization of stool frequency seen in 63% at Week 8 and 83% by Week 16. Complete biochemical data were available for 55 patients to Week 8, with a rate of biochemical response at Week 8 of 65%. A total of 42 patients were switched directly from tofacitinib to upadacitinib, of whom 31 (74%) had clinically active disease at baseline. There was no significant difference between clinical remission(88%vs82%,P= 0.39) and clinical response (85%vs81%,P= 0.55) in tofacitinib-exposed vs tofacitinib-naive patients at Week 8. IUS was per-formed on 18 patients at baseline and Week 8. The median BWT at base-line was 4.9 mm, which decreased to 2 mm at Week 8. The modifiedLimberg score was 0 in 6% at baseline and in 83% at Week 8. IUS findings showed 100% concordance with clinical response. Adverse events were seen in 20 patients (16%), with all but one being minor without a requirement for hospitalization and none leading to drug discontinuation. The one hospitalization was for acute severe UC shortly after upadacitinib commencement, which was treated with intravenous steroids and upadacitinib continued on discharge. The most common events noted were acne (n= 4) and nasopharyngitis (n= 4). No venous thromboembolism, systemic infection, or cardiovascular events were observed. Conclusion: This is the first Australian study showing that upadacitinib is effective and safe in a real-world setting for both biologic-naive and refractory patients with moderate to severe UC. Upadacitinib was also highly effective in tofacitinib-exposed patients.