Patients with Crohn’s disease who did not respond adequately to ustekinumab still achieved meaningful clinical, endoscopic, and radiographic improvement after switching to risankizumab in a multicenter Canadian cohort study, with 38% achieving clinical remission within one year.
“Increasingly, there are more therapies for Crohn’s disease and interleukin-23 antagonists have become a very important part of the therapeutic armamentarium,” one of the study authors, Christopher Ma, MD, MPH, of the Department of Medicine and Community Health Sciences at the Cumming School of Medicine, University of Calgary, Canada, told GI & Hepatology News. “However, there may be some hesitancy to use this class of treatment in patients who have previously been treated with ustekinumab, an IL-12/23 antagonist. In this multicenter study, we show that risankizumab is still effective for achieving clinically relevant symptomatic, endoscopic, and sonographic outcomes in Crohn’s disease, even after ustekinumab exposure. This observation was consistent in both patients who were primary or secondary non-responders to ustekinumab. This is important because it suggests that we should potentially think of IL-23 antagonists as a separate class of drug and mechanism of action that is unique to the IL-12/23 blockade.”
For the retrospective study, published in Gastroenterology, Dr. Ma and colleagues evaluated 148 adults with Crohn’s disease treated with risankizumab after prior ustekinumab exposure at tertiary inflammatory bowel disease referral centers at the University of Calgary and University of Alberta and followed them for a median of 56 weeks after risankizumab initiation. Nearly 90% had already not responded to at least one other advanced treatment besides ustekinumab, and more than 60% had tried three or more advanced therapies overall. Most patients had ileocolonic disease, while about one-third had stricturing disease and another one-third had penetrating disease.
At 52 weeks, 38% of patients achieved cumulative clinical remission, while 23% achieved endoscopic remission and 20% achieved radiographic remission based on intestinal ultrasound findings. Clinical response rates reached 69% at one year. Endoscopic response occurred in 53% of evaluated patients, while radiographic response occurred in 49%.
The investigators also observed significant reductions in inflammatory biomarkers, including fecal calprotectin and C-reactive protein, after risankizumab treatment.
The study addressed a growing clinical question as selective IL-23 inhibitors become more widely used in Crohn’s disease. Ustekinumab targets the interleukin-12/23 p40 subunit, whereas risankizumab selectively inhibits the interleukin-23 p19 subunit. Prior mechanistic studies have suggested IL-23 may be the dominant inflammatory driver in Crohn’s disease.
Dr. Ma and colleagues found that prior failure of ustekinumab did not necessarily predict failure of risankizumab. Primary nonresponse to ustekinumab, prior tumor necrosis factor antagonist exposure, disease phenotype, and duration of ustekinumab treatment were not significantly associated with lower likelihood of endoscopic or radiographic response after switching therapies.
Among patients who had no endoscopic improvement with ustekinumab, nearly 39% improved after switching to risankizumab and 26% achieved endoscopic remission.
One subgroup appeared more likely to benefit. Patients who had previously achieved endoscopic remission with ustekinumab before later losing response were nearly four times more likely to achieve an endoscopic response after switching to risankizumab.
The authors said the findings may help inform therapeutic sequencing decisions for physicians managing refractory Crohn’s disease. They noted that dose optimization of ustekinumab has shown relatively low endoscopic remission rates in prior studies, including the REScUE trial, in which about one in 10 patients achieved endoscopic remission after ustekinumab intensification.
In the current study, 41% of patients with secondary loss of response to ustekinumab achieved endoscopic or radiographic remission after switching to risankizumab.
The study used pragmatic real-world definitions to assess clinical and objective outcomes. Clinical response was defined as at least a 50% reduction in stool frequency or abdominal pain, while endoscopic response required at least a 50% reduction in Simple Endoscopic Score for Crohn’s Disease or resolution of large ulcerations. Sonographic response was defined by at least a 25% improvement in bowel wall thickness or physician global assessment.
Nonresponder imputation was used for patients discontinuing treatment because of adverse events, intolerance, or nonresponse. Endoscopic and radiographic outcomes included only patients who underwent follow-up colonoscopy or intestinal ultrasound evaluation.
The analysis had several limitations, including its retrospective design, possible referral bias associated with tertiary centers, and small numbers of patients undergoing endoscopic and sonographic follow-up. Follow-up intervals also reflected routine clinical care rather than protocolized assessments.
“In conclusion, risankizumab is a potentially effective option for patients with CD previously treated with ustekinumab, with meaningful cumulative rates of clinical and objective response observed in routine practice,” the authors wrote. “Prior endoscopic remission on ustekinumab identifies patients most likely to respond, although benefit is observed even among ustekinumab primary and secondary non-responders.”
No funding was provided for the study. Dr. Ma and several authors reported consulting fees, advisory roles, speaking fees, or research support from pharmaceutical companies including AbbVie, Janssen, Takeda, Pfizer, Eli Lilly, and Roche.