Risankizumab Induction, Maintenance Therapy Improves Clinical Remission Rates in UC

Findings from a pair of phase 3 randomized clinical trials are providing clinicians with an overview of the impact of treatment with risankizumab on rates of clinical remission in patients with moderately to severely active ulcerative colitis (UC).¹

Data from the induction trial, INSPIRE, and the maintenance trial, COMMAND, showed improved clinical remission rates with risankizumab compared to placebo and were the basis for the US Food and Drug Administration (FDA)'s approval of risankizumab for UC on June 18, 2024.^1,2

“Despite numerous therapies, treating ulcerative colitis is often difficult because of the challenge of any one treatment achieving a highly efficacious and durable response over time,” Gilaad Kaplan, MD, MPH, a professor of professor of medicine in the department of medicine and community health sciences at Cumming School of Medicine at the University of Calgary, wrote.³ “The absence of one clearly defining treatment for moderate to severe ulcerative colitis is, in part, the consequence of the multiple immunologic pathways involved in the pathogenesis of ulcerative colitis.”

Already boasting approvals for plaque psoriasis, psoriatic arthritis, and Crohn’s disease, the interleukin (IL)-23 specific inhibitor’s approval for UC was supported by findings from INSPIRE and COMMAND showing clinical remission, the primary endpoint in both the induction and maintenance studies, was achieved, along with endoscopic improvement, a key secondary endpoint.¹

INSPIRE

Conducted at 261 clinical centers in 41 countries, the induction trial enrolled patients 18- 80 years of age with a diagnosis of UC for ≥ 3 months with an adapted Mayo score of 5-9 points, an endoscopic subscore of 2-3 that was confirmed by central review, and a history of intolerance or inadequate response to conventional therapy alone, 1 or more advanced therapies, or a combination of conventional and advanced therapies. Of note, patients with prior exposure to p40 inhibitors or p19 inhibitors were excluded.¹

Participants were randomly assigned in a 2:1 ratio to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8, with randomization stratified by the presence of baseline corticosteroid use, baseline adapted Mayo score, and history of intolerance or inadequate response to advanced therapies. The primary outcome was clinical remission, determined using the adapted Mayo score and defined as a stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability at 12-week follow-up.¹

Of the 1430 patients screened for the induction trial, 977 were randomized and 975 received ≥ 1 dose of risankizumab (n = 650) or placebo (n = 325), administered intravenously. Among these patients, the mean age was 42.1 (Standard deviation [SD], 13.8) years and the majority were male (60.1%) and White (69.6%), with 98% of patients in risankizumab group completing 12-week follow-up compared with 92% in the placebo group.¹

At week 12, clinical remission rates were 20.3% for participants receiving 1200 mg of risankizumab and 6.2% for those receiving placebo (adjusted between-group difference, 14.0%; 95% CI, 10.0%-18.0%; P <.001). The most frequently reported adverse events were COVID-19 (4.8%) and anemia (3.4%) in the risankizumab group and colitis ulcerative (10.2%) and anemia (6.5%) in the placebo group. Investigators noted the rate of serious adverse events was 2.3% for risankizumab compared with 10.2% for placebo, and a single treatment-emergent death occurred in the risankizumab group due to respiratory failure caused by COVID-19 pneumonia.¹

COMMAND

Conducted at 238 clinical centers in 37 countries, the maintenance trial enrolled patients who had been enrolled in an induction trial and had an adequate response to risankizumab at 12- or 24-week follow-up. Participants were randomly assigned in a 1:1:1 ratio to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo every 8 weeks for 52 weeks, with randomization stratified by history of inadequate response to advanced therapy, last risankizumab induction dose, and clinical remission status at the last visit of the induction trial.¹

Like the induction study, the primary outcome was clinical remission, determined using the adapted Mayo score and defined by components of the score at 52-week follow-up.¹

Of the 584 patients randomized in the maintenance trial, 548 had an adequate clinical response to risankizumab at week 12 of the induction trial and were thus included in the primary efficacy population of the maintenance trial. In total, 179 patients were in the 180 mg risankizumab group, 186 were in the 360 mg risankizumab group, and 183 were in the placebo group. Among these patients, the mean age was 40.9 (SD, 14.0) years and the majority of patients were male (57.1%) and White (74.3%).¹

At week 52, the clinical remission rates were 40.2% for 180 mg risankizumab, 37.6% for 360 mg risankizumab, and 25.1% for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3%; 97.5% CI, 6.1%-26.6%; P <.001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2%; 97.5% CI, 4.0%-24.5%; P = .002). The most frequently reported adverse events among all treatment groups were colitis ulcerative (13.0% in the 180 mg risankizumab group; 13.8% in the 360 mg risankizumab group; 14.8% in the placebo group) and COVID-19 (8.8% in the 180 mg group; 13.3% in the 360 mg group; 11.7% for placebo). Investigators observed serious adverse events in 5.2% of the 180 mg group and 5.1% of the 360 mg group compared with 8.2% of the placebo group.¹

Investigators outlined multiple limitations to the findings from both INSPIRE and COMMAND, including the potential inflation of response rates during the maintenance trial due to continued risankizumab exposure from the induction trial; the lack of evaluation of patients with prior exposure to emerging therapies in the evolving inflammatory bowel disease treatment landscape; and the need for follow-up beyond 52 weeks.¹

“Risankizumab adds to a growing list of biological drugs and oral small molecules that have proven efficacy in treating patients with moderate to severe ulcerative colitis. The challenge that gastroenterologists face is determining the sequence of these therapies for patients with ulcerative colitis,” Kaplan concluded.³ “Future comparative effectiveness clinical trials are needed to sequence risankizumab in the treatment paradigm of ulcerative colitis.”

References

1. ^{Louis E, Schreiber S, Panaccione R, et al. Risankizumab for Ulcerative Colitis: Two Randomized Clinical Trials. JAMA. Published online July 22, 2024. doi:10.1001/jama.2024.12414}
2. ^{Brooks, A. FDA Approves Risankizumab (Skyrizi) for Ulcerative Colitis. HCPLive. June 18, 2024. Accessed July 22, 2024. https://www.hcplive.com/view/fda-approves-risankizumab-skyrizi-for-ulcerative-colitis}
3. ^{Kaplan, GG. Monoclonal Antibody Risankizumab for Ulcerative Colitis. JAMA. Published online July 22, 2024. doi:10.1001/jama.2024.8819}