Clinical utility of ustekinumab in Crohn's disease

Abstract

The introduction of anti-tumor necrosis factor (TNF) therapy marked an important milestone in the management of moderate-to-severe Crohn's disease (CD). However, there remains a pressing demand for alternative therapeutic options for patients with primary nonresponse, secondary loss of response, or intolerable side effects to conventional treatment and TNF antagonists. Ustekinumab (UST) is a fully human IgG1κ monoclonal antibody that inhibits the p40 subunit shared by the proinflammatory cytokines, the interleukin (IL)-12 and -23. This blockade leads to dampening of the inflammatory cascade and differentiation of inflammatory T cells. The clinical development program for UST in CD includes dose finding Phase II (Crohn's Evaluation of Response to Ustekinumab Anti-Interleukin-12/23 for Induction [CERTIFI]) and the pivotal Phase III (UNITI) trials that demonstrated both the clinical efficacy and safety in anti-TNF-naive and anti-TNF-exposed patients. Real-world evidence has further defined the role of UST in CD management. In this review, we discuss the mechanism of action of UST, describe the results of the randomized controlled trials with this agent, and review the real-world efficacy and safety data from observational cohorts. Finally, we identify areas of future research in the IL-12/23 inflammatory pathway and discuss the positioning of this novel therapeutic option in CD treatment algorithms.

Keywords: Crohn’s disease; interleukin; ustekinumab.

Figure 1

Structures of IL-12 and IL-23, their receptors and the site of action of UST. Notes: IL-12 is composed of both p40 and p35 subunits, while IL-23 is composed of p40 and p19 subunits. IL-12 receptor is composed of two subunits, such as IL-12Rβ1 and IL-12Rβ2. IL-23 receptor is composed of two subunits, such as IL-12Rβ1 and IL-23R. Abbreviations: IL, interleukin; IL-23R, IL-23 receptor; UST, ustekinumab.

Figure 2

Clinical response in Phase IIa trial of UST in population 1 (n=104 randomized patients). Notes: The primary endpoint (clinical response at week 8) was not met, and the trial was considered negative. However, a significant difference in clinical response was observed at weeks 4 and 6. Data from Sandborn et al. Abbreviation: UST, ustekinumab.

Figure 3

Clinical response rates at week 6 (induction) in the CERTIFI trial (primary outcome). Notes: Statistical significance reached in the UST 1 and 6 mg/kg groups. Data from Sandborn et al. Abbreviation: UST, ustekinumab.

Figure 4

Primary endpoint results of the UNITI-1 and UNITI-2 studies. Notes: Clinical response at week 6 was more prevalent in the UST-treated groups. In UNITI-1, P-values as compared to placebo were 0.002 (UST 130 mg) and 0.003 (UST 6 mg/kg). In UNITI-2, P-values as compared to placebo were <0.001 for both UST 130 mg and UST 6 mg/kg. Data from Feagan et al. Abbreviation: UST, ustekinumab.

Figure 5

Clinical remission rates at week 44 of the IM-UNITI maintenance study. Notes: In the pooled overall UST group, P=0.040 (q12 weeks) and P=0.005 (q8 weeks) for UST as compared to placebo. Among patients derived from the UNITI-1 induction trial, P=0.14 (q12 weeks) and P=0.10 (q8 weeks). Among patients derived from UNITI-2 trial, P=0.15 (q12 weeks) and P=0.02 (q8 weeks). Data from Feagan et al. Abbreviation: UST, ustekinumab.