Current research into new therapeutics for inflammatory bowel disease (IBD) focuses on targeted biologics and small molecules to attack specific molecular pathways that promote IBD pathologies. Upadacitinib is an oral, reversible inhibitor of Janus kinase (JAK) that is approved as induction or maintenance therapy for patients with moderately to severely active Crohn’s disease (CD) or ulcerative colitis (UC) who have had an inadequate response to 1 or more tumor necrosis factor (TNF) inhibitors.1,2 U-ACHIEVE and U-ENDURE, both phase 3 trials, demonstrated the superiority of upadacitinib (15 or 30 mg, daily) in comparison with placebo as maintenance therapy in patients with moderately to severely active UC or CD.3,4 To evaluate long-term safety outcomes, investigators conducted a post hoc analysis of patient data from the 2 trials.5 Treatment-emergent adverse events (AEs) were pooled from patients in both studies who responded to upadacitinib induction and then received placebo or upadacitinib as maintenance therapy.
The analysis included 746 patients from U-ACHIEVE and 673 from U-ENDURE. In a comparison of the placebo vs the upadacitinib cohorts, the rates of serious and severe treatment-emergent AEs were higher with placebo than with upadacitinib in both patients with UC and those with CD. The most frequently reported infections were nasopharyngitis (exposure-adjusted event rate [EAER], 11.6-14.2), upper respiratory infection (EAER, 6.8-7.3), and COVID19 (EAER, 6.9-7.6). Rates of serious infections were similar across treatment groups; however, herpes zoster was more common among patients treated with upadacitinib. In each upadacitinib treatment group (15 or 30 mg; 0.3/100 patient-years), 1 gastrointestinal perforation was observed, whereas 2 perforations were observed in the placebo group. Rates of venous thromboembolism were higher with 15 mg of upadacitinib (EAER, 1.0) or 30 mg of upadacitinib (EAER, 0.9) than with placebo (EAER, 0), all in patients with UC. The EAERs for malignancies excluding non-melanoma skin cancer were as follows: 0.6 in the group that received 15 mg of upadacitinib, 1.0 in the group that received 30 mg of upadacitinib, and 0.4 in the placebo group.
Another post hoc study evaluated outcomes from patients who had a CD activity index (CDAI) of at least 220 at baseline in the phase 3 U-EXCEED and U-EXCEL induction trials (n=857) or who achieved a clinical response (at least a 100-point reduction in the CDAI from baseline [CR-100]) in the phase 3 U-ENDURE maintenance trial of upadacitinib vs placebo (n=343).6 Among patients with a CDAI of at least 220 at baseline, higher rates of CDAI clinical remission (46.2% vs 22.5% in U-EXCEL; 35.9% vs 17.8% in U-EXCEED; P<.0001 for both) and of endoscopic response (45.5% vs 12.6% in U-EXCEL; 34.1% vs 3.4% in U-EXCEED; P<.0001 for both) were observed with upadacitinib induction than with placebo (Figure 1). Analysis of key secondary endpoints, including stool frequency/abdominal pain score clinical remission, CR-100, steroidfree clinical remission, and endoscopic remission, also showed significantly superior outcomes with upadacitinib vs placebo in this patient subgroup. No new safety signals emerged.
Figure 1.
U-EXCEL and U-EXCEED induction results among patients with CDAI ≥220 at BL.
BL, baseline; CDAI, Crohn’s Disease Activity Index; UPA, upadacitinib; wk, week.
Adapted from Rubin et al. Abstract P0732. Presented at: ACG 2023; October 20-25, 2023; Vancouver, British Columbia, Canada.6
Patients from U-ENDURE who were included in the analysis had achieved a CR-100 with upadacitinib induction therapy. At week 52 of maintenance therapy, the rates of CDAI clinical remission were 54.6% with upadacitinib (30 mg), 41.6% with upadacitinib (15 mg), and 14.4% with placebo (P<.0001), and the rates of endoscopic response were 41.2%, 27.8%, and 7.2%, respectively (P<.0001) (Figure 2). A higher proportion of patients treated with upadacitinib than with placebo achieved key secondary endpoints, including corticosteroid-free CDAI clinical remission, endoscopic remission, stool frequency/abdominal pain score clinical remission, and others.
Figure 2.
U-ENDURE maintenance results among patients who had CDAI ≥220 at induction BL and achieved CDAI ≥100 at maintenance wk 0.
BL, baseline; CDAI, Crohn’s Disease Activity Index; PBO, placebo; UPA, upadacitinib; wk, week.
Adapted from Rubin et al. Abstract P0732. Presented at: ACG 2023; October 20-25, 2023; Vancouver, British Columbia, Canada.6
References
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- Rubin DT, Loftus EV, Regueiro M Efficacy of upadacitinib in patients with Crohn’s disease activity index-based eligibility criteria: post hoc analysis of U-EXCEL, U-EXCEED, and U-ENDURE phase 3 trials. Abstract P0732. 2023. Presented at: ACG 2023 Annual Scientific Meeting; October 20-25. Vancouver, Canada.