Phillips, Charles M.

Abstract Background and Aims This post hoc analysis assessed the efficacy and safety of upadacitinib in patients with moderately to severely active ulcerative colitis stratified by corticosteroid use from the ulcerative colitis Phase 3 clinical trial programme. Methods Patients were randomised [1:2] to 8 weeks’ placebo or upadacitinib 45 mg once daily; Week 8 responders were re-randomised [1:1:1] to 52 weeks’ placebo or upadacitinib 15 or 30 mg daily. Corticosteroid dose was kept stable during induction but tapered according to a protocol-defined schedule [or investigator discretion] during maintenance Weeks 0–8. Efficacy outcomes and exposure-adjusted, treatment-emergent adverse event [TEAE] rates were assessed for induction and maintenance stratified by corticosteroid use at induction baseline. Results Overall, 377/988 [38%] patients were receiving corticosteroids at induction baseline [placebo, n = 133; upadacitinib 45 mg, n = 244] and 252 [37%] of the 681 clinical responders who entered maintenance were on corticosteroids at induction baseline [n = 84 for each treatment]. Similar proportions of patients receiving upadacitinib achieved clinical remission per Adapted Mayo Score with and without baseline corticosteroids at Weeks 8 and 52. The total proportion of patients re-initiating corticosteroids was higher with placebo [24/84;29%] vs upadacitinib 15 mg [16/81; 20%)] and 30 mg [11/81; 14%]. During induction, patients receiving corticosteroids at baseline had higher rates of TEAEs, serious TEAEs, and serious infections vs those not receiving corticosteroids; however, TEAE rates were similar during maintenance after corticosteroid withdrawal. Conclusions Upadacitinib is an effective steroid-sparing treatment in patients with moderately to severely active ulcerative colitis. Clinicaltrials.gov identifiers: NCT02819635; NCT03653026

Abstract Background We evaluated the health-related quality of life (HRQoL) benefits of upadacitinib (UPA) induction and maintenance treatment in a phase 3 study of patients with ulcerative colitis (UC) across a broad range of patient-centered outcomes. Methods Patients received UPA 45 mg once daily or placebo as induction treatment for 8 weeks. Patients who achieved clinical response were rerandomized to receive once daily UPA 15 mg, 30 mg, or placebo as maintenance treatment for 52 weeks. The percentages of patients reporting a clinically meaningful within-person change from baseline in the Ulcerative Colitis Symptoms Questionnaire, Inflammatory Bowel Disease Questionnaire, Work Productivity and Impairment Questionnaire, 36-Item Short Form Survey, and European Quality of Life-5 Dimension 5 Levels were evaluated at weeks 2 and 8 of induction and at weeks 0 and 52 of maintenance. Results Significant improvements from baseline in all HRQoL measures except the Work Productivity and Impairment Questionnaire–absenteeism were achieved with UPA (P < .001) vs placebo as early as week 2 of induction. These improvements were sustained at week 52 with significantly more patients treated with either 15 mg or 30 mg UPA vs placebo achieving meaningful within-person change in the Ulcerative Colitis Symptoms Questionnaire; Inflammatory Bowel Disease Questionnaire; overall work impairment, presenteeism, and activity impairment; both 36-Item Short Form Survey Physical and Mental Component Summaries; and European Quality of Life-5 Dimension 5 Levels (P < .001). Conclusions Induction treatment with UPA 45 mg significantly improved HRQoL measures. A significantly higher percentage of patients who responded to induction treatment with UPA maintained clinically meaningful improvements consistently across a wide range of HRQoL outcomes after 52 weeks of maintenance therapy with UPA (15 mg and 30 mg) compared with placebo. (ClinicalTrials.gov, Numbers: NCT02819635, NCT03653026).

Abstract Background Health-related quality of life (HRQOL) is reduced in patients (pts) with ulcerative colitis (UC). We report on the HRQOL benefits of maintenance treatment with upadacitinib (UPA), a selective and reversible Janus kinase inhibitor, in pts with moderately to severely active UC in the Phase, 3 multicentre, randomised, double-blind U-ACHIEVE maintenance study (NCT02819635). Methods This study included a primary analysis of, 451 pts who achieved clinical response following treatment with UPA, 45 mg once daily (QD) in two replicate, 8-week induction studies, U-ACHIEVE induction, and U-ACCOMPLISH (NCT03653026). In U-ACHIEVE maintenance, pts from both induction studies were re-randomised, 1:1:1 to receive QD UPA, 15 mg, UPA, 30 mg, or PBO. HRQOL outcomes evaluated included the percent of pts reporting a clinically meaningful within-person change (MWPC) from induction baseline to Week, 0 (maintenance baseline) and Week, 52 (end of maintenance) in a broad range of HRQOL measures, including Inflammatory Bowel Disease Questionnaire (IBDQ), Work Productivity and Impairment Questionnaire (WPAI), Short Form, 36 (SF-36), European Quality of Life-5 Dimensions, 5 Levels (EQ-5D-5L), and Ulcerative Colitis Symptoms Questionnaire (UC-SQ). Results A total of, 149, 148, and, 154 pts received PBO, UPA, 15 mg, and UPA, 30 mg QD, respectively, during maintenance. At Week, 0 of the maintenance study, there were no significant differences between UPA and PBO treatment groups in the percentage of pts reporting MWPC relative to induction baseline for most pt-reported outcomes (PROs) as all pts enrolled in maintenance were UPA clinical responders during IP. For IBDQ, a significantly greater proportion of pts achieved MWPC criteria (p<0.001) with UPA, 15 mg (68.9%) and UPA, 30 mg (78.6%) vs, 39.6% for PBO at Week, 52 (Figure, 1). Also, a significantly greater proportion of pts treated with either, 15 mg or, 30 mg UPA dosage vs PBO over, 52 weeks achieved MWPC for the WPAI domains (p≤0.01) of overall work improvement, presenteeism, and activity impairment (Figure, 2), in both physical and mental component summaries of SF-36 (p<0.001, Figure, 3), in EQ-5D-5L (p<0.001, Figure, 4), and in UC-SQ (p<0.001). A numerically greater proportion of pts receiving UPA, 30 mg vs, 15 mg achieved MWPC in most PROs at Week 52. Conclusion A significantly higher percentage of pts with moderately to severely active UC who responded to UPA induction therapy maintained clinically meaningful improvements with UPA, 15 mg of, 30 mg compared to PBO consistently across a broad range of HRQOL outcomes after, 52 weeks of maintenance treatment. These HRQOL aspects include IBD symptoms (IBDQ, UC-SQ), work productivity (WPAI), physical and mental functioning (SF-36), and general well-being (IBDQ, EQ-5D).

Abstract Background The oral, selective Janus kinase inhibitor upadacitinib (UPA) has demonstrated efficacy as induction and maintenance therapy in patients with moderately to severely active Ulcerative Colitis (UC) in a Phase 3 clinical programme comprising two identical induction trials (U-ACHIEVE Induction [NCT02819635] and U-ACCOMPLISH [NCT03653026]) and a maintenance study (U-ACHIEVE Maintenance). This analysis assessed the impact of baseline corticosteroid (CS) use on the efficacy and safety of UPA in patients in these trials. Methods Patients were randomised 2:1 to UPA 45 mg once daily (QD) or placebo (PBO) for 8 weeks. Patients who achieved a clinical response at Week 8 were re-randomised 1:1:1 to UPA 15 mg QD, UPA 30 mg QD or PBO for 52 weeks. Here, we report induction and maintenance endpoints and safety data stratified by baseline CS use. Results Baseline demographics and disease characteristics were generally well balanced across treatment groups, regardless of baseline CS use. Clinical remission rates among patients receiving UPA 45 mg induction therapy did not differ by baseline CS use (Figure 1A). In the induction period, rates of treatment-emergent adverse events of special interest (AESI), including serious and opportunistic infections, were increased in the UPA 45 mg plus baseline CS group compared with the PBO and UPA without baseline CS groups (Table 1). In the maintenance study, CS tapering was mandated. CS-free remission at Week 52 (defined as clinical remission, per Adapted Mayo Score, and CS free for ≥90 days immediately prior to Week 52) was significantly increased with UPA 30 and 15 mg compared with PBO (both p<0.001; Figure 1B). Among patients receiving UPA maintenance, rates of treatment-emergent AESIs in the baseline CS versus no baseline CS groups were 33% versus 39% and 27% versus 35% in the UPA 30 mg and UPA 15 mg groups, respectively. Malignancy, major adverse cardiovascular events, venous thromboembolic events, and serious and opportunistic infections were reported infrequently in patients receiving UPA (Table 1). Conclusion This post hoc analysis suggests that, in patients with moderately to severely active UC, UPA is superior to PBO in conferring CS-free remission. Baseline CS use was not associated with any apparent efficacy benefit and carried a potential increased safety risk. These results suggest that achieving early disease control with UPA and without CS use is an optimal treatment strategy for this population.

Abstract Background Upadacitinib (UPA), an oral, reversible JAK inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, or tyrosine kinase 2 (TYK2), 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 trials, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026). This analysis evaluated the efficacy of UPA on early symptomatic improvement for the first 14 days, using pooled data from U-ACHIEVE Induction and U-ACCOMPLISH. Methods U-ACHIEVE and U-ACCOMPLISH were multicentre, double-blind, PBO-controlled trials that enrolled patients who have had moderately to severely UC with an Adapted Mayo Score of 5 to 9 points and centrally reviewed endoscopy subscore of 2 to 3. A total of 998 patients were randomized to receive UPA 45mg once daily (QD) (n=658) or PBO (n=328) for 8 weeks (wks) in a 2:1 ratio. First dose of study drug was administered on Day 0. Improvement in symptoms including stool frequency subscore (SFS), rectal bleeding subscore (RBS), abdominal pain, and bowel urgency were analysed from daily symptom diary data. Multivariate regression analysis was used to determine if early changes in UC symptoms could be used to evaluate a potential correlation with patients’ likelihood of achieving clinical response or clinical remission per Adapted Mayo score at the end of induction. Results Baseline characteristics were similar between both treatment groups. Patients treated with UPA 45 mg QD experienced significant improvement in daily symptoms, with significantly more subjects achieving SFS≤1 (p<0.001), RBS of 0 (p<0.05), and SFS of 0 (p<0.05) as early as day 1 and maintained through day 14 (Figure 1). A significantly higher percentage of patients who received UPA 45 mg QD compared to PBO, achieved abdominal pain=0 and the absence of bowel urgency within 3 days of beginning treatment through day 14 (p<0.05). Multivariate analysis revealed that patients who achieved day 7 SFS≤1 (OR 2.42, 95% CI, 1.53–3.82) were more likely to attain clinical response (Table). Patients who attained day 7 SFS≤1 (OR 2.53, 95% CI 1.59–4.00) or day 7 bowel urgency absent (OR 2.40, 95% CI 1.52–3.79) were more likely to achieve clinical remission at week 8. Conclusion UPA 45 mg QD significantly improved UC symptoms as early as day 1, providing patients with rapid symptom relief. Patients who achieved early symptom improvement were more likely to attain clinical remission or clinical response at week 8. [Clinicaltrials.gov, U-ACHIEVE Induction (NCT02819635) and U-ACCOMPLISH (NCT03653026)]