Selective Blockade of IL-23 with Risankizumab Shows Promise as Therapy for Crohn's Disease

“Today, I’ll be presenting the first ever, phase 2 proof-of-concept interim trial data for risankizumab, formerly known as BI 655066, in the treatment of moderate-to-severe Crohn’s disease,” said Brian Feagan, MD, PhD, Director of Robarts Clinical Trials in London, Ontario, Canada, at a presentation at Digestive Disease Week 2016, a joint meeting of the American Academy for the Study of Liver Diseases (AASLD), American Gastroenterological Association (AGA), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).

“Among those cytokines involved in Crohn’s disease pathogenesis, IL-23 is a key regulatory of the Th17 and Th22 pathways that contribute to inflammatory cytokine production and tissue inflammation this disease,” Feagan explained. Risankizumab (BI 655066) is a humanized monoclonal antibody that selectively inhibits IL-23 through specific targeting of the IL-23 p19 subunit.

“Recent trials with ustekinumab, a monoclonal antibody that targets the p40 subunit shared by IL-23 and IL-12, have shown that the inhibition of these cytokines is an effective potential treatment option for Crohn’s disease. However, it is not clear whether this efficacy is driven by inhibition of IL-12 or IL-23,” he explained.

This was a phase 2, randomized, placebo-controlled trial of two different intravenous (IV) doses of risankizumab. Three treatment periods included a 12-week, double-blind IV induction period, a 14-week, open-label IV re-induction/washout period, and a 2-week subcutaneous maintenance period. During the induction period, 121 patients who had previously been treated with a TNF antagonist or conventional CD therapy and who had endoscopically confirmed, clinically active disease (CD Activity Index [CDAI] score of 220 or higher) and a CD Endoscopic Index of Severity (CDEIS) score of 7 or higher (4 or higher for patients with isolated ileitis) were randomized to receive either 200 mg or 600 mg of risankizumab or matching placebo at Weeks 0, 4, and 8.

The primary endpoint was clinical remission (CDAI <150) at Week 12. Secondary endpoints included clinical response, endoscopic remission/response, and deep remission.

The majority of patients were female, with a mean age of 38.1 years and mean CDAI and CDEIS scores of 306.8 and 13.4, respectively. The vast majority of patients (94.2%) had previously been exposed to one or more tumor necrosis factor (TNF) antagonists.

After 12 weeks of treatment, approximately twice as many patients treated with 600 mg risankizumab, many of whom had previously failed treatment with one or more TNF antagonists, achieved clinical remission (no symptoms or very mild symptoms of disease) compared with placebo (36.6% vs. 15.4%, p=0.025). Clinical response rates were also about twice that for 600 mg-treated patients compared with placebo (41.5% vs. 20.5%, p=0.037). Finally, endoscopic remission was achieved by 14.6% and 19.5% of patients treated with 200 mg and 600 mg, respectively, compared with 2.6% (p=0.056 and p=0.017 for 200 mg and 600 mg, respectively). Overall, the adverse event (AE) profile for risankizumab was similar to that of placebo, with no dose-related increase in AEs and fewer severe and serious AEs in the 600-mg risankizumab group.

“These results are particularly encouraging because of the difficult-to-treat population included in this study. Our patients had endoscopically confirmed moderate or more severe disease activity at study entry and the majority had previously failed treatment with one or more TNF antagonists. These results indicate that the selective blockade of IL-23 with risankizumab may be a promising new therapeutic approach for this serious chronic disease that warrants further investigation,” he concluded.