Xie, Wenhui

Abstract Background Upadacitinib (UPA), an oral selective and reversible JAK inhibitor, demonstrated significantly greater efficacy compared with placebo (PBO) for induction of remission in patients with moderately to severely active ulcerative colitis (UC) in two phase 3 induction trials. Aims Evaluate safety and efficacy of 52 weeks of UPA 15 mg QD (UPA15) and 30mg QD (UPA30) compared to placebo in patients achieving clinical response following UPA 45 mg treatment in the induction trials. Methods The primary analysis (n=451) evaluated efficacy and safety of UPA15 and UPA30 compared to PBO as maintenance therapy. The primary endpoint was clinical remission via adapted Mayo score at wk 52. Ranked secondary endpoints included endoscopic improvement, maintenance of clinical remission, corticosteroid-free clinical remission, maintenance of endoscopic improvement, endoscopic remission, maintenance of clinical response and Histologic-endoscopic mucosal improvement (HEMI). Results Baseline characteristics were similar between all treatment groups. Both UPA15 and UPA30 met the primary endpoint, and all secondary endpoints. Significantly greater percentages of patients receiving UPA15 and UPA30 vs. PBO achieved clinical remission (42.3% and 51.7%, vs. 12.1%), endoscopic improvement (48.7% and 61.6%, vs. 14.5%), maintenance of clinical remission (59.2% and 69.7%, vs. 22.2%), corticosteroid-free clinical remission (57.1% and 68.0%, vs. 22.2%), maintenance of endoscopic improvement (61.6% and 69.5%, vs. 18.9%), endoscopic remission, (24.2% and 25.9%, vs. 5.6%) and HEMI (34.8% and 49.3%, vs. 11.8%) (p<0.001 for all endpoints). UPA15 and UPA30 were both well-tolerated and no new safety signals were observed. Rates for serious adverse events (AEs) and AEs leading to treatment discontinuation were similar between UPA15 and UPA30 groups and lower compared to the PBO group. Most common AEs were nasopharyngitis and creatine phosphokinase elevation among UPA groups and UC exacerbation within the PBO group (30.2%). Herpes zoster was only reported in UPA groups (3.9%-4.1%). Similar rates of malignancy excluding NMSC were seen within all groups (0.7%-1.3%). MACE were only reported among patients receiving PBO (0.7%), while VTE were only found with UPA30 (1.3%). Conclusions In patients responding to UPA induction therapy, both UPA15 and UPA30 were safe and effective as maintenance treatment at 52 wk for all primary and secondary endpoints. Patients receiving UPA30 responded approximately 10% better for most endpoints compared to those receiving UPA15. Both doses were well-tolerated, with no new safety signals observed. Funding Agencies AbbVie

Abstract Background Upadacitinib (UPA) is a selective and reversible Janus kinase inhibitor.U-ACCOMPLISH is one of two phase 3 induction trials that evaluated the safety and efficacy of UPA 45 mg once daily (QD) in adults with ulcerative colitis (UC). Methods U-ACCOMPLISH was a multicentre, randomized, double-blind, placebo-controlled trial (NCT03653026) that enrolled patients with moderate-to-severe UC (defined as adapted Mayo score 5–9 with centrally read endoscopic score 2–3) who had inadequate response, loss of response, or intolerance to aminosalicylates, immunosuppressants, corticosteroids and/or biologics. Patients were randomized 2:1 to UPA 45 mg QD or placebo (PBO) for 8 weeks. At week 8, responders entered the maintenance phase and non-responders entered the extended treatment period to receive open-label UPA 45 mg QD for additional 8 weeks.The primary endpoint (clinical remission per adapted Mayo Score) and ranked secondary endpoints including symptomatic, endoscopic– histologic evaluations from the 8-week PBO-controlled period are reported here. Non-responder imputation incorporating multiple imputation for missing data due to COVID-19 are reported. Results 522 patients were randomized (UPA, n=345; PBO, n=177); the intent-to-treat population included 341 patients in UPA and 174 patients in PBO group. Baseline demographics and disease characteristics were similar between groups; 50.7% and 51.1% were biologic inadequate responders in UPA and PBO groups, respectively (Table 1). A significantly higher proportion of patients receiving UPA 45 mg QD (33.5%) versus PBO (4.1%) achieved the primary endpoint (adjusted treatment difference: 29.0% [23.2, 34.7]; P<0.001). A significantly higher proportion of patients receiving UPA versus PBO also achieved all ranked secondary endpoints (all P<0.001; Figure 1).Serious adverse events were reported by 3.2% and 4.5% of patients in UPA and PBO groups, respectively (Table 2). Similar rates of serious infection were observed in both groups (0.6%); 2 events each of herpes zoster and opportunistic infection were reported in UPA group. No active tuberculosis, malignancy, adjudicated major adverse cardiovascular events, or deaths were reported in the study. One patient with venous thromboembolism (deep vein thrombosis and pulmonary embolism) and 1 patient with gastrointestinal perforation were reported in the placebo group. Conclusion In U-ACCOMPLISH, 8-week UPA 45 mg QD induction treatment led to statistically significant improvements in clinical, endoscopic, and combined endoscopic-histologic endpoints. The treatment was well tolerated, and the safety profile and AE prevalence was comparable with previous studies of UPA with no new safety signals identified.

Abstract Background Adalimumab (ADA) is efficacious and well tolerated in adult patients with ulcerative colitis (UC).1,2 SERENE-UC (NCT02065622) is a study evaluating higher ADA dosing regimens from which induction study results have previously been reported3; here, we report data from the maintenance study. Methods This Phase 3, double-blind, randomised, multicentre study evaluated higher vs. standard ADA dosing regimens for induction and maintenance therapy in adult patients with moderately to severely active UC. Following completion of the induction study at Week 8, all patients were re-randomised 2:2:1 to ADA 40 mg every week (40 EW), ADA 40 mg every other week (40 EOW), or exploratory ADA 40 mg with therapeutic drug monitoring (TDM) regimens, stratified by induction treatment regimen, clinical response status at Week 8, and clinical remission (CRem) status at Week 8 among Week 8 responders. Efficacy endpoints were evaluated in Week 8 responders (ITT-RP) unless indicated differently. The primary efficacy endpoint was proportion of patients achieving CRem (full Mayo Score ≤2 with no subscore >1) at Week 52. The endoscopic component of the Mayo Score was scored via central reading. Non-responder imputation was used for missing values. Comparisons between 40 EW and 40 EOW dosing regimens used the Cochran–Mantel–Haenszel test adjusted for stratification. Safety assessment included a collection of adverse events (AEs), vital signs, and laboratory data. Results Of 852 patients in the Global (ex-Japan) induction study, 757 were re-randomised at Week 8 and 371 were included in the ITT-RP. In the ITT-RP, induction baseline demographics and disease characteristics were generally balanced across the 3 treatment arms; range across arms for mean UC disease duration was 6.2–7.8 years, 6.8–11.7% had prior infliximab use, and 62.5–63.5% were receiving corticosteroids. The overall mean ADA exposure was 252.2 days. The table displays results for efficacy endpoints. The observed safety profile was similar between maintenance treatment arms, including AEs of special interest (generally <1% across arms). Conclusion In the Global (ex-Japan) study of SERENE-UC, CRem at Week 52 was numerically higher among Week 8 responders in patients receiving ADA 40 EW compared with 40 EOW maintenance regimens (∆ = 10.5%), but not statistically significant. Higher maintenance treatment with 40 EW was generally safe and well tolerated with a similar safety profile to 40 EOW. No new long-term safety concerns were observed. References

Abstract Background Anaemia is a frequent complication in patients with Crohn’s disease and ulcerative colitis (UC), and patients who respond to treatment generally show improvement in anaemia. Decrease in haemoglobin (Hgb) levels and anaemia may be associated with Janus kinase (JAK) inhibitors. Upadacitinib (UPA), an oral JAK1 selective inhibitor, has demonstrated favourable dose-dependent efficacy in patients with moderately to severely active UC.1 This analysis of data from the U-ACHIEVE study addressed effects of UPA treatment on Hgb levels in patients with UC. Methods U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with moderately to severely active UC were randomised to receive 7.5, 15, 30, or 45 mg UPA or PBO once daily (QD) for 8 weeks. Hgb levels were measured for all groups at baseline (BL) and weeks 2, 4, 6, and 8. Mean change from BL was calculated for each group. p-values for comparison between UPA and PBO groups were calculated using one-way ANOVA; no multiplicity adjustment was applied. Percentage of patients with Hgb values grade 2 (15–20 g/l Hgb decrease from BL), grade 3 (<80 g/l Hgb level or 21–29 g/l Hgb decrease from BL), and grade 4 (<70 g/l Hgb level or >29 g/l Hgb decrease BL) anaemia were determined for all treatment groups using the Common Terminology Criteria for Adverse Events version 5. Adverse events (AE) were reported by investigators. Results Included in the analysis were 250 patients (mean age ± SD, 42.3 ± 14.2 years; disease duration, 8.2 ± 2.5 years). At BL, most treatment groups had similar mean Hgb levels, except for the 15 mg UPA group, which had significantly lower Hgb levels vs. PBO group (Table). Increased or stable mean levels of Hgb at week 8 vs. BL were observed in most UPA treatment groups. The PBO group had the greatest decrease in Hgb vs. BL at week 8 compared with UPA treatment groups (Figure). Grade ≥2 anaemia was reported in 17.4% of patients receiving PBO and 14.4% of all patients receiving UPA (14.9%, 12.2%, 12.0%, and 17.9% of patients receiving 7.5, 15, 30, and 45 mg UPA, respectively). Grade ≥3 anaemia was reported in 8.7% of patients receiving PBO and 5% of all patients receiving UPA (6.4%, 6.1%, 6.0%, and 1.8% of patients receiving 7.5, 15, 30, and 45 mg UPA, respectively). One subject receiving 7.5 mg QD UPA had grade 4 anaemia. AE of anaemia was reported in 6.5% of patients receiving PBO and in 2.1%, 8.2%, and 3.8% of patients receiving 7.5, 15, and 30 mg UPA, respectively, but not in the 45 mg UPA group. Conclusion Decreased Hgb levels over time were observed more frequently in the PBO group. The maintenance of Hgb levels in patients receiving UPA was likely because of improvement of underlying UC. Reference