In a recent study published in The New England Journal of Medicine, researchers discuss the results of a randomized clinical trial (RCT) comparing the therapeutic efficacy of risakizumab and ustekinumab for the treatment of moderate-to-severe Crohn’s disease.

Study: Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn’s Disease. Image Credit: vitstudio / Shutterstock.com

Current treatment options for Crohn’s disease

Crohn’s disease is a type of chronic inflammatory bowel disease (IBD) that can affect any part of the human digestive tract. Oral administration of tumor necrosis factor (TNF) inhibitors is the first line of treatment for moderate-to-severe Crohn’s disease; however, TNF inhibitors are associated with a wide range of adverse side-effects, with some patients also exhibiting an inadequate response to TNF inhibitors. Thus, there remains an urgent need to develop alternative biologic agents with different modes of actions to treat this debilitating disease.

Interleukin-23 (IL-23) is a proinflammatory cytokine comprising a p40 subunit shared with IL-12 and a unique p19 subunit that plays a key role in skin, joint, and gastrointestinal inflammation. Ustekinumab and risankizumab are humanized monoclonal antibodies that selectively bind to p40 and p19 subunits, respectively. Previous clinical trials have indicated the therapeutic efficacy of these antibodies against plaque psoriasis, psoriatic arthritis, and Crohn’s disease.

In the current study, researchers evaluate the efficacy and safety of risankizumab and ustekinumab in patients with moderate-to-severe Crohn’s disease who were previously unresponsive to TNF inhibitor-based treatments.

Study design

This phase III clinical trial was conducted at 187 sites in 28 countries. Adult patients with moderate-to-severe Crohn’s disease who experienced unacceptable side-effects or were unresponsive to at least one TNF inhibitor-based treatment were eligible to participate in the trial.

Patients were randomly assigned to receive either the standard dose of risankizumab or ustekinumab for 48 weeks. Two primary treatment outcomes were tested sequentially, of which included clinical remission at week 24 and endoscopic remission at week 48.

Clinical remission was analyzed in the first 50% of patients for the assessment of noninferiority of risankizumab to ustekinumab. Endoscopic remission was analyzed in all patients to determine of superiority of risankizumab to ustekinumab. Safety was assessed in all patients who received at least one dose of risankizumab or ustekinumab.

A total of 520 patients were enrolled in the trial, 255 and 265 of whom received risankizumab or ustekinumab, respectively. About 90% and 72% of patients in the risankizumab and ustekinumab groups completed all assigned treatments, respectively.

The superior efficacy of risankizumab

At week 24, clinical remission occurred in 58% of risankizumab-treated patients and 39% of ustekinumab-treated patients. The analysis of primary treatment outcomes at week 48 revealed that endoscopic remission of the disease occurred in 31% and 16% of risankizumab- and ustekinumab-treated patients, respectively, thus indicating the superior efficacy of risankizumab as compared to ustekinumab.

Further analysis revealed that risankizumab was more effective than ustekinumab for all secondary treatment outcomes, including clinical and endoscopic remission, as well as glucocorticoid-free clinical and endoscopic remission, at week 48. A mandatory glucocorticoid tapering schedule was incorporated during the second week of the trial to measure clinically meaningful reduction of glucocorticoid use.

Risankizumab more effective than ustekinumab in improving daily stool frequency, abdominal pain, mucosal healing, and health-related quality of life. A lower incidence of hospitalization due to Crohn’s or any other disease was observed in the risankizumab treatment group as compared to that in the ustekinumab treatment group.

Safety assessment

The percentages of patients who experienced any adverse event or a severe adverse event, including serious infections or hepatic events, were comparable between the two treatment groups. However, the risk of serious adverse events related to worsening of underlying Crohn’s disease was lower in the risankizumab treatment group as compared to ustekinumab recipients.

The most commonly reported adverse event was coronavirus disease 2019 (COVID-19) in both groups. No anaphylactic reactions, serious hypersensitivity, active tuberculosis, or deaths were reported in either treatment group.

Significance

Risankizumab appears to be more effective than ustekinumab in achieving clinical and endoscopic remission in patients with moderate-to-severe Crohn’s disease. The higher therapeutic efficacy of risankizumab may be attributed to its increased affinity for IL-23, superior ability to inhibit IL-23, or the role of IL-12 in protecting the gut microenvironment from inflammation.     

Regarding safety profile, the study findings indicate that both risankizumab and ustekinumab have an acceptable side-effect profile.