Risankizumab superior to ustekinumab in moderate-to-severe Crohn’s disease

Risankizumab outdoes ustekinumab in achieving endoscopic remission at week 24 in patients with moderate-to-severe Crohn’s disease (CD), as well as in other clinical, endoscopic, and quality of life (QoL) outcomes, as shown by the results of the phase IIIB SEQUENCE trial presented at AIBD 2023.

In addition, risankizumab is not inferior to ustekinumab in achieving clinical remission at week 24. The safety profiles of both therapies were also consistent with previously published results, according to the investigators, led by Laurent Peyrin-Biroulet, Nancy University Hospital, Vandoeuvre-les-Nancy, France.

SEQUENCE was an open-label, multicentre, randomized, efficacy assessment-blinded study. It included 527 patients with moderate-to-severe CD (CD activity index [CDAI], 220‒450, endoscopic evidence of mucosal inflammation, and average daily stool frequency ≥4 and/or average daily abdominal pain score ≥2) who had failed treatment with antitumour necrosis factor (anti-TNF) therapies.

Peyrin-Biroulet and colleagues randomly assigned CD patients to receive either risankizumab or ustekinumab for 48 weeks. They stratified participants based on the number of anti-TNF therapies failed and baseline steroid use. A mandatory steroid taper was initiated at week 2.

Clinical remission (CDAI, <150) at week 24 (noninferiority of risankizumab to ustekinumab in 50 percent of patients) and endoscopic remission (Simple Endoscopic Score for CD ≤4 and at least 2-point reduction vs baseline and no subscore >1 in any variable) at week 48 (superiority) were the primary endpoints. Other clinical, endoscopic, and QoL outcomes, as well as adverse events (AEs), were also examined.

Of the patients, 520 were assessed for efficacy: 255 for risankizumab and 265 for ustekinumab. More patients treated with risankizumab completed the study relative to those who received ustekinumab (89.4 percent vs 74.0 percent). Both primary endpoints were achieved. [AIBD 2023, abstract S1]

Risankizumab demonstrated noninferiority to ustekinumab in achieving clinical remission at week 24 (58.6 percent vs 39.5 percent; Δ, 18.4, 95 percent confidence interval [CI], 6.6‒30.3). “This endpoint was also analysed post hoc to test for superiority and achieved nominal p<0.01,” the investigators said.

Endoscopic rates at week 48 were 31.8 percent and 16.2 percent for risankizumab and ustekinumab, respectively (Δ, 15.6 percent, 95 percent CI, 8.4‒22.9; p<0.0001 for superiority).

Secondary outcomes

Likewise, risankizumab displayed superiority to ustekinumab for all other endpoints: clinical remission at week 48 (60.8 percent vs 40.8 percent; Δ, 19.7 percent, 95 percent CI, 11.3‒28.1), endoscopic response at week 48 (45.1 percent vs 21.9 percent; Δ, 23.3 percent, 95 percent CI, 15.4‒31.2) and week 24 (45.2 percent vs 26.4 percent; Δ, 18.9 percent, 95 percent CI, 10.9‒26.9), steroid-free (SF) endoscopic remission at week 48 (31.4 percent vs 15.5 percent; Δ, 15.9, 95 percent CI, 8.8‒23.1), and SF clinical remission at week 48 (60.8 percent vs 40.4 percent; Δ, 20.1 percent, 95 percent CI, 11.7‒28.4; p<0.0001 for all for superiority).

Patients treated with risankizumab also showed a significantly greater mean change from baseline in Inflammatory Bowel Disease Questionnaire total score at week 24 (52.4 vs 40.2; Δ, 12.2, 95 percent CI, 6.6‒17.8) and week 48 (56.5 vs 42.4; Δ, 14.1, 95 percent CI, 8.2‒20.0; p<0.0001 for all).

In terms of safety, exposure-adjusted AE rates did not significantly differ between the two therapies (341.2 vs 282.7 events per 100 patient-years). Serious AEs and AEs leading to treatment discontinuation were numerically lower with risankizumab than ustekinumab. No between-group differences were seen in serious infection and hepatic events rates.

However, one case of malignancy was observed in each treatment arm, and one adjudicated major adverse cardiovascular event occurred in one patient receiving ustekinumab. No deaths were reported.

“Risankizumab is a safe and effective treatment for CD,” the investigators said.