Risankizumab versus Ustekinumab for Crohn's Disease: When less is more
Review by Prof. Vishal Sharma (India)
Study Summary
In a randomized trial, 527 patients with moderate to severe Crohn’s disease, who did not respond previously to anti-TNF therapy, were randomized to receive ustekinumab or risankizumab. The randomization was stratified for the number of previous anti-TNF therapies and the use of steroids. At 24 weeks, the assessment of the primary endpoint, clinical remission (CDAI<150) for 50% of the study population, risankizumab was noninferior to ustekinumab (58.6% versus 39.5%). For endoscopic remission (SES-CD of ≤4 and a decrease of ≥2 points from baseline) at 48 weeks, risankizumab was superior to ustekinumab (31.8% versus 16.2%). More patients in the ustekinumab arm discontinued therapy and this was most frequently due to lack of efficacy. Risankizumab performed better than ustekinumab for other secondary endpoints (clinical remission and endoscopic response at 48 weeks, steroid free remission).
Commentary
While a number of advanced therapies are becoming available for the management of inflammatory bowel disease, the appropriate positioning of these therapies in a treatment algorithm is difficult because of limited head-to-head trials. Ustekinumab, a humanized IgG1 monoclonal antibody targets IL12 and IL23 by blocking the p40 subunit shared by both of these cytokines while risankizumab is a p19 blocking antibody that blocks the action of IL23 only. The SEQUENCE trial seems to confirm the superiority of p19 blockage to p40 blockage in Crohn’s disease - something which was already demonstrated in the setting of psoriasis. This would help in positioning these therapies in anti-TNF refractory Crohn’s disease and, most particularly, in settings where access and affordability to these therapies are not an issue. For most of the world though, access and affordability, rather than efficacy will define the choice and sequencing of therapy. The trial had some limitation especially the open label design but the blinded central reading of the endoscopic responses would have ensured unbiased assessment of endoscopic response. It is also unclear if the findings are generalizable to all of IBD (including ulcerative colitis) or to bio-naïve Crohn’s disease. However, this important trial breaks new ground and emphasizes that future IBD trials for new therapies should feature an active control arm in order to help the clinician optimally position a new advanced therapy in the management cascade.
Citation
Peyrin-Biroulet L, Chapman JC, Colombel JF, Caprioli F, D'Haens G, Ferrante M, Schreiber S, Atreya R, Danese S, Lindsay JO, Bossuyt P, Siegmund B, Irving PM, Panaccione R, Cao Q, Neimark E, Wallace K, Anschutz T, Kligys K, Duan WR, Pivorunas V, Huang X, Berg S, Shu L, Dubinsky M; SEQUENCE Study Group. Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn's Disease. N Engl J Med. 2024 Jul 18;391(3):213-223. doi: 10.1056/NEJMoa2314585. PMID: 39018531.
Link
https://pubmed.ncbi.nlm.nih.gov/39018531/
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