Risankizumab Beats Ustekinumab for Steroid-Free Crohn’s Remission

Key Takeaways

• In adults with moderately to severely active Crohn’s disease, prior inadequate response or intolerance to at least 1 anti-TNF therapy, and corticosteroid use at baseline in SEQUENCE, risankizumab was associated with higher corticosteroid-free clinical, endoscopic, and health-related quality-of-life outcomes than ustekinumab over 48 weeks.
• Corticosteroid discontinuation was more common with risankizumab than ustekinumab by week 8 (75.9% vs 59.2%) and week 48 (86.2% vs 57.7%).
• Week 48 CDAI remission, SF/APS remission, and endoscopic remission all favored risankizumab, while week 24 CDAI remission was numerically higher but not statistically significant.
• Exposure-adjusted TEAE rates were generally similar overall, while selected adverse events were numerically higher among baseline corticosteroid users regardless of treatment.

Moderately to severely active Crohn’s disease after anti-tumor necrosis factor (TNF) failure often leaves patients trying to maintain symptom and endoscopic control while tapering corticosteroids that are not suitable for long-term maintenance. Risankizumab and ustekinumab were compared head to head in SEQUENCE under a mandatory corticosteroid taper that began at week 2, and one subgroup focused on patients who entered treatment already using corticosteroids.

Investigators conducted a post hoc analysis of the SEQUENCE post hoc analysis, a phase 3b, multicenter, open-label, randomized, efficacy assessment-blinded trial that ran for 48 weeks. The intention-to-treat population included 520 randomized and treated adults with moderately to severely active Crohn’s disease and prior inadequate response or intolerance to at least 1 anti-TNF therapy; this subgroup included 129 baseline corticosteroid users, with 58 assigned to risankizumab and 71 to ustekinumab, after 1:1 allocation stratified by prior anti-TNF count and baseline glucocorticoid use. Risankizumab was given as 600 mg intravenously at weeks 0, 4, and 8, then 360 mg subcutaneously every 8 weeks from week 12, while ustekinumab was given as a single weight-based intravenous induction dose, then 90 mg subcutaneously every 8 weeks from week 8, and the mandatory corticosteroid taper began at week 2. Clinical endpoints included Crohn disease activity index (CDAI) remission and stool frequency/abdominal pain score (SF/APS) remission; endoscopic assessment used the simple endoscopic score for Crohn’s disease (SES-CD); health-related quality of life was measured with the inflammatory bowel disease questionnaire (IBDQ); and safety was summarized as exposure-adjusted treatment-emergent adverse events (TEAEs). Corticosteroid-free meant no corticosteroids at the corresponding study visit, with a stricter week 48 analysis requiring at least 90 days without corticosteroid use; categorical endpoints used nonresponder imputation with multiple imputation for missing data, and adjusted risk differences with 95% confidence intervals and nominal P values were reported.

Week 48 corticosteroid-free symptom remission favored risankizumab. Corticosteroid-free CDAI remission occurred in 56.9% with risankizumab versus 31% with ustekinumab; adjusted difference 25.4 percentage points (95% CI 8.7-42.1), P < .01. Corticosteroid-free SF/APS remission was 53.4% versus 23.9%; adjusted difference 29.2 percentage points (95% CI 12.9-45.4), P < .001. Corticosteroid discontinuation favored risankizumab early and remained separated by week 48, while week 24 CDAI remission numerically favored risankizumab without reaching statistical significance. The symptom-based remission pattern was more pronounced by week 48.

Week 48 corticosteroid-free endoscopic remission also favored risankizumab. Corticosteroid-free endoscopic remission was 32.8% with risankizumab versus 12.7% with ustekinumab; adjusted difference 20.2 percentage points (95% CI 6.0-34.5), P < .01. Corticosteroid-free endoscopic response, mucosal healing, deep remission, and week 48 IBDQ response also favored risankizumab, and IBDQ remission was numerically greater; week 24 endoscopic response and mucosal healing moved in the same direction. The week 48 clinical and endoscopic pattern was similar when corticosteroid-free required at least 90 days without corticosteroid use. Exposure-adjusted TEAE rates were generally similar between groups, while serious infections, herpes zoster, hypersensitivity, and injection site reactions were numerically higher in patients using corticosteroids at baseline regardless of treatment; no active tuberculosis, serious hypersensitivity, or adjudicated anaphylactic reaction was reported.

This post hoc subgroup analysis included only the minority of SEQUENCE participants who were using corticosteroids at study entry, which left a smaller subgroup and more variable efficacy estimates. The authors noted that the open-label design could influence subjective outcomes such as CDAI and IBDQ, although objective endoscopic outcomes moved in the same direction. They also characterized the subgroup P values as nominal in this international multicenter trial.

In anti-TNF-experienced adults with moderately to severely active Crohn’s disease who were using stable oral corticosteroids at protocol-limited doses and had not previously received other approved biologics or targeted small molecules, the authors reported higher corticosteroid-free clinical, endoscopic, and selected quality-of-life outcome rates with risankizumab than with ustekinumab over 48 weeks, alongside generally similar overall exposure-adjusted TEAE rates.

Clinician Questions

Which Crohn’s disease patients were represented in the SEQUENCE corticosteroid-sparing subgroup?

The SEQUENCE corticosteroid-sparing subgroup included 129 of 520 randomized and treated adults with moderately to severely active Crohn’s disease who had prior inadequate response or intolerance to at least 1 anti-TNF therapy and were using corticosteroids at baseline. Entry criteria included a CDAI of 220-450, an average daily stool frequency of at least 4 and/or an abdominal pain score of at least 2, and an SES-CD of at least 5, or at least 4 for isolated ileal disease.

How did SEQUENCE define corticosteroid-free remission at week 48?

In SEQUENCE, the main subgroup analyses defined corticosteroid-free remission as being off corticosteroids at the week 48 study visit. Investigators also ran a stricter week 48 analysis that required at least 90 days without corticosteroid use before that visit, and the clinical and endoscopic remission pattern remained similar under that definition.

What happened if corticosteroid doses had to be increased during taper in SEQUENCE?

In SEQUENCE, tapering began at week 2, and investigators could increase corticosteroids back up to the baseline dose if response was inadequate. If a patient’s corticosteroid dose rose above baseline, that patient was counted as a nonresponder for efficacy from that point forward while remaining in the safety population.

Why do the endoscopic findings matter in this open-label Crohn’s disease analysis?

The endoscopic findings matter because the authors noted that treatment awareness in an open-label trial could influence subjective measures such as CDAI and IBDQ. Objective endoscopic outcomes moved in the same direction as the symptom-based results, which the authors cited as corroboration of the overall pattern.

Recommended Reading

• For more on IL-12/23 and IL-23 therapy in Crohn’s: IBD Care Reimagined: Personalized, Proactive, and Target-Driven Management
• For more on Crohn’s biologic treatment strategy: IBD Masterclass: Choosing the Right IBD Therapy - A Patient-Clinician Connection