Gil Melmed, MD, Reviews the Role of Interleukin Inhibitors in IBD

Findings suggest interleukin (IL)-23 inhibitors such as risankizumab, guselkumab, and mirikizumab, are efficacious in the treatment of inflammatory bowel disease (IBD), Gil Y. Melmed, MD, told the audience at the Advances in Inflammatory Bowel Diseases virtual meeting. In addition, he noted, IL-23 may also be incrementally effective compared to IL-12/23.

Dr Melmed is the codirector of the IBD center and associate director of the Karsh Division of Digestive and Liver diseases at Cedars-Sinai Medical Center in Los Angeles, California. 

“Incorporate shared decision-making, consistent communication, and consideration of the patient perspective into the care strategy of patients with IBD,” Dr Melmed advised during his presentation. He also evaluated key efficacy and safety data for approved and emerging IL-12/23 and IL-23p19 inhibitors for the management of IBD.

When selecting the appropriate therapy for patients with IBD, Dr Melmed suggested breaking it down to drug-specific considerations and patient-specific considerations. For drug considerations, investigate the efficacy iof the drug and the safety, he noted. Ask questions such as what the indication for the drug is, how quickly does it work, how durable is the drug in long-term, should we go for combination therapy or monotherapy, should we consider therapeutic drug monitoring, and when and how to sequence the drug in the patient disease cycle.

For patient considerations, don’t just think of patient characteristics, Dr Melmed advised. “Also consider disease characteristics,” he said. Consider individual characteristics such as age, comorbidities, patient preferences, insurance access, and other costs; and disease characteristics such as Crohn disease (CD) vs ulcerative colitis (UC), disease behavior and complications, disease severity, extraintestinal manifestations, and considerations of previous treatment success or failure, should all factor into these decisions.

Dr Melmed reviewed the dilemma of whether to switch to a second anti-tumor necrosis factor (TNF) therapy or to switch to another mechanism of action when patients with IBD do not respond to anti-TNF therapy. Multiple studies have found that anti-TNF-naïve patients often do better with other mechanisms of action.

Based on the findings of the study by Brian Feagan, MD, and colleagues published in the New England Journal of Medicine, ustekinumab “had a significantly higher rate of response than did those receiving placebo among patients with moderately to severely active CD.” Patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram at week 6 achieved significantly higher rates of response than patients receiving placebo (34.3%, 33.7%, and 21.5% respectively)

In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, compared to 35.9% of those receiving placebo (p=0.005 and p=0.04, respectively.) The occurrences of adverse events in both groups were similar.

Dr Melmed addressed the ongoing debate over whether patients with IBD treated with vedolizumab or ustekinumab should receive concomitant therapy with immunomodulators. A meta-analysis of 6 randomized controlled trials and 27 cohort studies found that “combining vedolizumab or ustekinumab with an immunomodulator is no more effective than monotherapy in induction or maintenance of remission,” Dr Melmed said.

Risankizumab was found to be a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active CD. By offering a new therapeutic option, Dr Melmed said, the future course of IBD may change altogether. In the ADVANCE and MOTIVATE trials, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164; and endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients.

The LUCENT trial investigated the clinical effect of mirikizumab among patients with moderate to severely active UC. LUCENT-1 focused on the induction outcomes of 1162 patients randomized 3:1 to intravenous 300 mg mirikizumab or placebo every 4 weeks for 12 weeks. LUCENT-2 focused on the maintenance outcomes of 544 patients re-randomized 2:1 to subcutaneous mirikizumab 200 mg or placebo every 4 weeks for 40 weeks (52 weeks of continuous treatment)

Patients on mirikizumab achieved clinically meaningful improvement in bowel urgency and remission at Weeks 12 and 52 than patients who were on placebo. Mirikizumab was successful in achieving other significant outcomes such as clinical, corticosteroid-free, endoscopic, and symptomatic remission; clinical response; normalized fecal calprotectin and C-reactive protein; and improved quality of life.

Another option available to patients is guselkumab— a selective p19 interleukin-23 antagonist that is already approved for the treatment of plaque psoriasis and psoriatic arthritis. Findings of a phase 2, double-blind, placebo-controlled study called GALAXI-1 found greater clinical and endoscopic improvements at week 12 in the group of patients taking guselkumab vs those taking placebo. The patients were randomized in 5 groups to intravenous guselkumab 200 mg, 600 mg, or 1200 mg at weeks 0, 4, and 8; intravenous ustekinumab approximately 6 mg/kg at week 0 and 90 mg subcutaneously at week 8; or placebo.

The VEGA study group compared the clinical outcomes of guselkumab plus golimumab combination therapy to guselkumab or golimumab monotherapy among patients with UC. The randomised, double-blind, controlled, proof-of-concept trial, included adults from 54 hospitals and academic medical centers from 9 countries.

The 214 patients were then randomly assigned (1:1:1) combination therapy (subcutaneous golimumab 200 mg at week 0, subcutaneous golimumab 100 mg at weeks 2, 6, and 10, and intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab monotherapy 100 mg every 8 weeks for 32 weeks), golimumab monotherapy (subcutaneous golimumab 200 mg at week 0 followed by subcutaneous golimumab 100 mg at week 2 and every 4 weeks thereafter for 34 weeks), or guselkumab monotherapy (intravenous guselkumab 200 mg at weeks 0, 4, and 8, followed by subcutaneous guselkumab 100 mg every 8 weeks thereafter for 32 weeks).

“At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group; and 53 (75%) of 71 patients in the guselkumab monotherapy group,” Dr Melmed said. The most common adverse events were ulcerative colitis, upper respiratory tract infection, headache, anaemia, nasopharyngitis, neutropenia, and pyrexia. No deaths, malignancies, or cases of tuberculosis were reported during the combination induction period. Based on these findings, Dr Melmed said, “combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone.”

In summary, IL-23 (risankizumab,guselkumab,mirikizumab) are efficacious for CD and UC and may be incrementally effective compared to IL-12/23. Additionally, IL-23 inhibitors are highly effective for psoriasis, but they hold promise in the treatment of gastrointestinal issues among patients too.

—Priyam Vora

Melmed GY. Optimized care for patients with IBD: The potential benefits of interleukin inhibitors. Presented at: Advances in Inflammatory Bowel Diseases virtual meeting.