Risankizumab Eases Moderate to Severe Crohn’s Disease

Risankizumab (Skyrizi) was safe and effective for patients with moderate to severe Crohn’s disease (CD), according to two phase III induction trials and a maintenance trial.

All co-primary endpoints were met at week 12 for the induction trials, ADVANCE and MOTIVATE, even at different IV doses, reported Geert D’Haens, MD, of the Amsterdam University Medical Center in the Netherlands, and colleagues, writing in The Lancet.

In ADVANCE, risankizumab led to more clinical remission, as determined by CD activity index (CDAI) or stool frequency and abdominal pain scores, as well as better endoscopic response compared with placebo (P<0.0001 for all):

• Clinical remission by CDAI: 45% at 600 mg, 42% at 1,200 mg, 25% with placebo
• Clinical remission by stool/pain criteria: 43% at 600 mg, 41% at 1,200 mg, 22% with placebo
• Endoscopic response: 40% at 600 mg, 32% at 1200 mg, 12% with placebo

Rates were similar in MOTIVATE with doses of 600 mg and 1,200 mg versus placebo, respectively, for clinical remission based on CDAI (42%, 40%, 20%) or stool/pain (35%, 40%, 19%) and for endoscopic response (29%, 34%, 11%).

Maintenance treatment in the FORTIFY trial with 360 mg of subcutaneous risankizumab led to higher rates of CDAI-based (52% vs 41%) and stool/pain-based clinical remission (52% vs 40%) and endoscopic response (47% vs 22%) versus placebo at 52 weeks. CDAI-based clinical remission and endoscopic response were also numerically but not significantly higher for the 180-mg subcutaneous maintenance dose versus placebo for stool/pain-based clinical remission.

Biologics can be effective for inflammatory bowel disease, but many patients with more severe disease do not respond, lose efficacy over time, or develop side effects leading to discontinuation, which leaves them requiring additional therapies.

The selective monoclonal antibody risankizumab uses a new mechanism that targets the p19 subunit of the cytokine interleukin (IL)-23. The drug was approved in 2019 to treat moderate to severe plaque psoriasis, and showed superiority over ustekinumab (Stelara), a p40 inhibitor that targets IL-12 and IL-23.

But it has been in development for CD as well after showing efficacy with a 180-mg subcutaneous dose among patients with moderate to severe CD in a prior phase II trial, D’Haens’ group noted.

ADVANCE, MOTIVATE, and FORTIFY are “the first reports to show the therapeutic effect of IL-23-specific inhibition in phase 3 trials for patients with Crohn’s disease, and to include the co-primary endpoints of clinical remission and endoscopic response,” Toshifumi Hibi, MD, of the Kitasato Institute Hospital in Tokyo, stated in an accompanying editorial. “The concept of IL-23 inhibition is based on the fact that raised concentrations of IL-23 are present in the mucosa of patients with Crohn’s disease and genome-wide association studies have shown a correlation between gene polymorphisms of the IL-23 receptor and the development of Crohn’s disease.”

D’Haens and colleagues analyzed data on moderate to severe CD patients from the multi-center, randomized, induction trials, ADVANCE with 850 participants and MOTIVATE with 569. In these trials, patients were randomized (2:2:1 in ADVANCE and 1:1:1 in MOTIVATE) to treatment with 600 mg or 1,200 mg of IV risankizumab or placebo once every 4 weeks for 12 weeks, with a 140 day follow-up period.

Patients ages 16 to 80 were enrolled if they did not respond to biologics or conventional therapeutics (ADVANCE) or did not respond to biologics alone (MOTIVATE).

If patients achieved clinical response with risankizumab from ADVANCE or MOTIVATE, they could enroll in the global, maintenance withdrawal FORTIFY substudy 1 trial. FORTIFY consists of four substudies to date.

In the multi-center, double-blind substudy 1 of FORTIFY, 542 patients were re-randomized 1:1:1 to receive 180 mg or 360 mg of subcutaneous risankizumab or placebo once every 8 weeks. Those who did not achieve clinical response by induction week 12 were further enrolled in an “exploratory induction period 2,” but could still enroll in FORTIFY if they achieved clinical response at 24 weeks, with results to be reported at a future date.

Patients had similar demographics and baseline characteristics among groups. Mean CD duration was 8.8 years in ADVANCE and 11.7 in MOTIVATE. Across the trials, the average age was 37 to 40 and 43-57% of participants were men.

“Promising and favorable benefit-risk profiles were reported, opening the possibilities of a highly anticipated new treatment option for patients with Crohn’s disease who still have unmet needs,” Hibi said.

For safety, overall adverse events (AEs) were similar across induction trials at rates of 48-66%. Of the three patients who died, two were placebo patients from ADVANCE. One was a MOTIVATE trial patient who received 1,200 mg of risankizumab and died from acute respiratory failure from invasive lung cancer deemed unrelated to the intervention. Common AEs for risankizumab (≥ 5%) included nasopharyngitis and headache. Five serious infections occurred in ADVANCE and three in MOTIVATE, but none were related to risankizumab.

About 72%-73% of maintenance patients had AEs, with the most common being worsening of CD, arthralgia, and headache. No deaths occurred.

The authors acknowledged limitations to the data, including that corticosteroids were stabilized during induction, the studies lacked an active comparator and prolonged pharmacological effects among withdrawal placebo patients.