Efficacy of Upadacitinib in Patients With One or More Prior Surgical Procedures for Crohn’s Disease: A Post Hoc Analysis of U-EXCEL, U-EXCEED, and U-ENDURE Phase 3 Trials
AIBD 2023
Background:
Nearly 50% of patients with Crohn’s disease (CD) undergo surgical intervention within 10 years of diagnosis.1 The post-operative setting remains poorly studied and poorly characterized. Here we evaluated the efficacy of upadacitinib (UPA), an oral Janus kinase inhibitor, versus placebo (PBO) for treatment of patients with moderate to severe CD and prior CD-related surgeries.
Methods:
This post hoc analysis evaluated patients from the U-EXCEED and U-EXCEL studies with ≥1 prior CD-related surgeries, including (but not limited to) bowel resection, ostomy, strictureplasty, abscess drainage (ie, abdominal, pelvic, perineal), fistulotomy, or seton placements. Clinical remission (CR) per CD Activity Index (CDAI < 150) and per stool frequency (SF)/abdominal pain score (APS) (average daily very soft/liquid SF ≤2.8 and average daily APS ≤1.0, neither greater than baseline), endoscopic response (Simple Endoscopic Score for CD [SES-CD] decrease >50% from baseline [or, for patients with baseline SES-CD=4, at least 2-point reduction from baseline]), and endoscopic remission (SES-CD ≤4 and a ≥2-point reduction from baseline and no subscore >1 in any individual variable) were assessed at induction week (wk) 12 (UPA 45mg QD [UPA45], N=287; PBO, N=140) and maintenance (U-ENDURE) wk52 (UPA 15mg QD [UPA15], N=62; UPA 30mg QD [UPA30], N=59; PBO, N=65). Non-responder imputation incorporating multiple imputation was used to handle missing data due to COVID-19. Nominal P values were calculated by the Chi-square test.
Results:
Demographic and baseline disease characteristics were generally similar across treatment groups. 48.5% of patients had ≥2 prior CD-related surgical procedures and 72.1% had prior bowel resection. With UPA45 versus PBO, patients with prior CD-related surgeries had higher rates of CDAI CR (32.7% versus 20.1%; Δ12.5 [95% CI: 3.9, 21.2], P< 0.01) and SF/APS CR (30.0% versus 12.1%; Δ17.8 [10.2, 25.4], P=0.0001), endoscopic response (23.7% versus 5.7%, Δ18.0 [11.7, 24.2], P< 0.0001), and endoscopic remission (9.8% versus 2.1%, Δ7.6 [3.4, 11.8], P< 0.01) at wk12. At wk52, UPA15 and UPA30 response rates were higher versus PBO: CDAI CR (UPA15, 22.6% [Δ11.8 {-1.0, 24.7}], and UPA30, 39.0% [Δ28.2 {13.7, 42.8}], versus PBO, 10.8%, P< 0.001, UPA30 versus PBO) and SF/APS CR (21.0% [Δ11.7 {-0.6, 24.1}] and 39.0% [Δ29.8 {15.5, 44.0}] versus 9.2%, P=0.0001, UPA30 versus PBO), endoscopic response (12.9% [Δ9.8 {0.5,19.2}] and 29.5% [Δ26.4 {13.9, 38.9}] versus 3.1%, P< 0.05, UPA15 versus PBO, P=0.0001, UPA30 versus PBO), and endoscopic remission (9.7% [Δ5.1 {-3.9, 14.0}] and 20.5% [Δ15.8 {4.3, 27.4}] versus 4.6%, P< 0.001, UPA30 versus PBO); a dose effect was observed. Patients with bowel resections, ostomy, or surgery or procedure for stricture (wk12: PBO, N=99; UPA45, N=218; wk52: PBO, N=43; UPA15, N=43; UPA30, N=44) demonstrated significant, albeit generally lower, response rate differences for UPA versus PBO, except for CDAI CR, UPA45 versus PBO, endoscopic response, UPA15 versus PBO, and endoscopic remission, UPA30 versus PBO . No new safety signals were identified in patients with prior CD-related surgeries.
Conclusions:
UPA induction and maintenance treatment was efficacious in patients with prior CD-related surgeries, with greater efficacy observed with the UPA30 maintenance dose. A higher maintenance dose may be more appropriate for patients with prior CD-related surgeries. Future prospective evaluation of this concept is merited.
