The Last 5 Years of Research on Ustekinumab in Crohn Disease

A review of literature published over the last 5 years on ustekinumab in Crohn disease (CD) summarized 42 clinical studies on the efficacy and safety of ustekinumab products, including biosimilars, and comparisons to other biologics.

CD, a chronic inflammatory disorder of the gastrointestinal tract, along with ulcerative colitis (UC), is referred to as inflammatory bowel disease (IBD). CD can lead to serious complications, including increased risk of cancers, and is often accompanied by extraintestinal manifestations affecting a variety of body systems.

Monoclonal antibodies targeting tumor necrosis factor (TNF)-alpha “significantly changed” the treatment of CD, allowing for more effective control of chronic inflammation, the authors wrote. The development of additional biologic therapies has increased the treatment options for patients with CD, such as ustekinumab, a human monoclonal antibody targeting the p40 subunit of interleukins (IL)-12 and -23.

Clinical trials on ustekinumab have shown that ustekinumab is a “valuable treatment option” for CD, particularly in patients who have experienced failure of previous treatments, according to the reviewers. For example, the UNITI-1 study evaluated ustekinumab in patients who had previous treatment failure on TNF inhibitors, and UNITI-2 in patients who experienced failure on conventional treatments such as immunosuppressants or glucocorticosteroids. In UNITI-1, approximately 34% of patients receiving ustekinumab achieved a clinical response at 6 weeks compared to 21.5% of the placebo group.

In UNITI-2, just over 50% of patients achieved a clinical response compared to 29% of patients receiving placebo. Differences between groups in both studies were significant. A long-term extension of another clinical trial showed remission in about 30% of patients after 5 years, 29% of those receiving ustekinumab every 12 weeks and 34% of those receiving ustekinumab every 8 weeks. Remission rates were somewhat higher in patients not previously treated with anti-TNF biologics.

The STARDUST trial evaluated a treat-to-target approach, including early endoscopy, monitoring of biomarkers and clinical symptoms, and therapy intensification when inflammation persisted, compared to standard of care in patients with moderate to severe CD treated with ustekinumab. No significant differences were observed between groups in endoscopic response (38% vs 30%), endoscopic remission (11% vs 15%), mucosal healing (14% vs 17%), and clinical remission (62% vs 70%); however, clinical response was significantly greater in the standard of care group (68% vs 78%).

According to the authors, ustekinumab has a “favorable” safety profile. Common side effects include headache, fatigue, nasopharyngitis, upper respiratory infections, and fever. Predictive factors associated with better outcomes in response to ustekinumab therapy identified in recent studies included shorter disease duration, higher eosinophil counts, ustekinumab levels of 1.12 μg/mL or greater, and ileal microvessel length greater than 1.7 µm.

Quality of life improvements in patients with CD have been demonstrated in both adult and pediatric patients by reducing symptoms, decreasing fatigue, and improving daily and social functioning. The authors noted differences between adult and pediatric populations: the ustekinumab dosing regimen is weight dependent for children. Whereas both populations have shown improvements in clinical outcomes, pediatric populations have shown a higher rate with fewer serious adverse events.

Recent studies have compared ustekinumab to other biologics. One study found 4% greater clinical remission with ustekinumab compared to adalimumab, whereas endoscopic lesions improved similarly in both groups. In another study, ustekinumab was comparable to risankizumab at 24 weeks, but risankizumab was superior at 48 weeks for inducing endoscopic remission. Another found risankizumab was superior for inducing endoscopic remission after failure on a previous biologic. In select cases, risankizumab may be a better treatment option than ustekinumab, the authors commented. In a comparison to infliximab, no significant differences were found in clinical remission between the 2 biologics, but infliximab was superior for inducing endoscopic response and remission.

The reviewers added that about 30% of biologic-naive patients do not respond to induction therapy with ustekinumab, and almost half of initial responders eventually experience loss of response. Thus, they emphasized “the need for individualized, biomarker-driven treatment strategies in optimizing outcomes for patients with CD,” given the critical gaps in understanding of drug durability, immunogenicity, and predictive biomarkers.

Available ustekinumab biosimilars include ABP 654 (Wezlana) and FYB202 (Otulfi), which were both found to be similarly safe and effective to the reference product in pharmacokinetic and comparative clinical trials. ABP 654 has also shown lower immunogenicity compared to the reference product.

Altogether, the research from the last 5 years “has demonstrated robust efficacy and safety” of ustekinumab for treating CD, in particular for patients who had experienced failure of previous therapies, the reviewers wrote. They added that real-world data has confirmed findings from clinical trials, with approximately one-third of patients achieving corticosteroid-free clinical remission after 2 years of treatment.

Furthermore, they added that ustekinumab treatment promotes mucosal healing, fistula closure, and improvement of extraintestinal manifestations. Ustekinumab has shown a “relatively low” rate of discontinuation and improvements in quality of life, although more long-term observational studies are required, as data beyond five years of follow-up is limited.

Reference

Piecuch D, Hańczyk E, Kopciał S, Pawelec N, Mazur W, Kornatowska K. Ustekinumab in the treatment of crohn’s disease—a narrative review on clinical efficacy and safety profile. Pharmacy. 2025;13(3):73. doi:10.3390/pharmacy13030073