Ustekinumab is currently the only anti-interleukin therapy approved for the treatment of ulcerative colitis, but given the superior performance of risankizumab in CD patients, it will be interesting to see data regarding its efficacy in UC.
As more advanced therapies are approved for the treatment of inflammatory bowel disease (IBD), insights into optimal positioning of therapies have grown increasingly important. The new phase 3b SEQUENCE study offers randomized controlled trial data comparing efficacy and safety of 2 medications approved for moderate to severe Crohn’s disease (CD), ustekinumab and risankizumab. Both act by blocking cytokine signaling that plays an important role in CD pathogenesis. Ustekinumab, the first available medication of this class, blocks the cytokines interleukin-12 (IL-12) and IL-23. Risankizumab, on the other hand, selectively blocks only IL-23. Following initial loading with an intravenous formulation (one intravenous dose for ustekinumab and three intravenous doses for risankizumab), both are given subcutaneously for maintenance dosing. Of note, maintenance risankizumab is administered via an on-body injector.
To be included in the SEQUENCE study, patients needed to be diagnosed with moderate to severe CD refractory to ≥1anti-tumor necrosis factor (TNF) medication such as infliximab or adalimumab. For the purposes of this study, moderate to severe CD was defined clinically as a CD activity index (CDAI) of 220-450 with ≥4 bowel movements per day and/or moderate to severe abdominal pain and was defined endoscopically as a Simple-Endoscopic Score for CD of ≥6 excluding the narrowing component (≥4 for isolated ileal disease). Endoscopy reports were scored by the site investigator with confirmation by a central reader, who was blinded to the study treatment.
Patients were randomized in a 1:1 fashion to either risankizumab (n = 255) or ustekinumab (n = 265). With respect to baseline demographics and disease characteristics, mean age was 38 years, approximately 50% of patients were female, mean disease duration was 9.4 years, approximately 22-26% of patients were on corticosteroids, and disease location was a mix of ileal (approximately 17%), colonic (40%), and ileocolonic (43%).
Primary endpoints were CDAI remission at week 24 and endoscopic remission at week 48. Secondary endpoints include endoscopic remission at week 24, clinical and endoscopic remission at week 48, and steroid-free clinical and endoscopic remission at week 8.
Risankizumab demonstrated non-inferiority to ustekinumab for clinical remission at week 24 (59% of patients on risankizumab were in clinical remission compared to 39.5% of patients on ustekinumab), and statistically significant superiority to ustekinumab for endoscopic remission at week 48 (31.8% of patients in remission on risankizumab compared to 16.2% of patients on ustekinumab). With respect to secondary endpoints, risankizumab demonstrated superiority across all recorded endpoints. There were no notable differences with respect to rates of treatment emergent adverse events and risankizumab had numerically fewer patients with adverse events of special interest during the study period, such as opportunistic infections or injection site reactions.
Overall, this was a well-designed study that provides key insights regarding positioning of risankizumab versus ustekinumab. Applicability to patients who do not meet the inclusion criteria (for example, patients naïve to biologic therapy) is more limited, but certainly in patients with inflammatory CD refractory to anti-TNF agents the data suggests it makes sense to position risankizumab over ustekinumab. Cost and insurance coverage unfortunately may be potential barriers to this, in which case whichever therapy is most accessible to the patient should be the one prescribed. Of note, ustekinumab is currently the only anti-interleukin therapy approved for the treatment of ulcerative colitis (UC), but given the superior performance of risankizumab in CD patients, it will be interesting to see data regarding its efficacy in UC.