Future Directions for Ustekinumab Biosimilars in Crohn Disease

The authors of a review article on the future of ustekinumab biosimilars for treating Crohn disease (CD) discussed key challenges, including a lack of data in CD and opportunities to improve access to treatment.

The authors of a review article on the future of ustekinumab biosimilars for treating Crohn disease (CD) discussed key challenges, including a lack of data in CD and opportunities to improve access to treatment. | Image credit: sdecoret - stock.adobe.com

CD, under the category of inflammatory bowel disease (IBD), is a chronic inflammatory condition of the gastrointestinal tract. The advanced therapeutic options for moderate to severe CD, biologics targeting tumor necrosis factor (TNF)-α (infliximab, adalimumab, and certolizumab), integrins (vedolizumab and natalizumab), and interleukins (ustekinumab), have become “the primary financial burden associated with IBD management,” the authors said.

Ustekinumab is a monoclonal antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23. The reference product (Stelara) was first approved by the FDA and European Medicines Agency (EMA) in 2009. Both agencies approved ustekinumab for treating CD in 2016.

Ustekinumab can be used in biologic-naive patients and those who have had treatment failure on another biologic. However, the authors said that due to high costs, ustekinumab is usually reserved for situations in which a patient has had treatment failure on 1 or more anti-TNF biologics. The originator’s patent is nearing expiration, which opens the possibility of ustekinumab biosimilars that could reduce costs, increase access to therapy, and allow for earlier use of ustekinumab in the course of CD treatment.

“Robust evidence” shows that anti-TNF biosimilars are clinically equivalent to the reference product (Humira), the reviewers said. For ustekinumab biosimilars, comparable efficacy, safety, immunogenicity, and pharmacokinetics to the reference product have been demonstrated; however, their approval for CD is based on extrapolation, “and there is no real-world data available yet for this indication.”

The first ustekinumab biosimilar, ABP 654 (Wezlana), was approved by the FDA in November 2023. AVT04 (Uzpruvo) was approved by the EMA and FDA in 2024, making it the first ustekinumab biosimilar approved in Europe. Additional ustekinumab biosimilars are in development. For example, Celltrion’s CT-P43 is supported by a phase 3 randomized controlled trial (RCT) showing comparable efficacy to the originator in moderate-to-severe plaque psoriasis. Marketing authorization applications for Dong-A ST's DMB-311535 and Fresenius Kabi and Formycon's FYB20236 have been accepted by the EMA and will soon be entering the market.

Overall, according to the reviewers, ustekinumab biosimilars have shown similar pharmacokinetic features, safety profiles, efficacy, and immunogenicity compared to the reference product in studies on healthy subjects and those on patients with psoriasis. Real-world studies could “increase the confidence of gastroenterologists when adopting ustekinumab biosimilars to treat CD patients.”

The authors commented that although there are several biologics available, there is no “globally validated therapeutic algorithm” for treating patients with moderate to severe CD. TNF inhibitors are “generally considered the first-line therapy as they are safe and effective drugs and biosimilars are available which make them accessible.” However, a trial comparing ustekinumab and adalimumab found they were equally effective in patients with CD, and a better safety profile, tolerability, and persistence were observed for ustekinumab. “Based on these data, ustekinumab could emerge as a leading choice in CD,” the reviewers said.

Additional recently approved treatment options for CD therapy include the IL-23 inhibitor risankizumab. One trial found risankizumab superior to ustekinumab for achieving endoscopic remission in patients with CD who were previously treated with anti-TNF biologics, but another found no differences between mirikizumab and ustekinumab effectiveness in CD. The reviewers said more head-to-head trials will be necessary “to define the positioning of selective IL-23 inhibitors” in CD treatment. Since risankizumab biosimilars are not yet available, among IL-23 inhibitors, ustekinumab biosimilars have a cost advantage.

The reviewers concluded that ustekinumab biosimilars “could be considered as first-line therapy for patients with IBD requiring advanced treatment,” increasing access and changing the drug’s positioning in the CD treatment algorithm. They added that real-world studies of ustekinumab biosimilars in IBD are needed to confirm long-term safety data.

Reference

D'Amico F, Bencardino S, Gonçalves A, Allocca M, Furfaro F, Zilli A, Parigi TL, Fiorino G, Peyrin-Biroulet L, Danese S. Unlocking hope: The future of ustekinumab biosimilars in Crohn's disease treatment. United European Gastroenterol J. 2025;13(2):186-200. doi:10.1002/ueg2.12682