Treating Challenging Moderate to Severe Crohn Disease With IL-12/IL-23 Inhibition

Crohn disease (CD) and ulcerative colitis are the prototypical conditions that define inflammatory bowel disease (IBD), a chronic disorder characterized by immune-driven inflammation that leads to mucosal damage of varying depth and intensity along the entire gastrointestinal tract. Data from the Global Burden of Diseases, Injuries, and Risk Factors Study, conducted in 195 countries between 1990 and 2017, showed IBD increasing in prevalence, although plateauing over the past 5 years (Figure).1 Substantial variation in the burden of IBD has been reported in different countries and regions, with the highest age-standardized prevalence rate reported in high-income countries and the lowest rates in lower-income countries.1



Crohn disease is a lifelong IBD with onset at any age; however, the predominant age at diagnosis is 20 to 30 years.2,3 The prevalence of CD shows similar global variation, with higher prevalence in the United States, Canada, New Zealand, the United Kingdom, Western Europe, and Scandinavian countries and lower prevalence in Africa, Asia, and Eastern European countries.2

No cure and a challenge to treat, but progress is being made

Clinical symptoms of CD range from mild to severe, with onset that can be gradual or sudden. Clinical manifestations include diarrhea, fever, abdominal pain, weight loss, and  complications that include fistula, abscess, and intestinal obstruction.4 As CD is currently without a cure and typically requiring a lifetime of care, treatment aims to achieve and maintain disease remission and, ultimately, mucosal healing with improvement in quality of life. However, treatment goals are rarely achieved and patient management is challenging and often inadequate, particularly patients with moderate to severe disease.

Prior to the introduction of biologic agents, the traditional approach to treating CD involved indiscriminate immunosuppression with corticosteroids and immunomodulators.5 For more than a decade now, development of therapies targeting specific immunologic pathways has changed the CD treatment landscape. Tumor necrosis factor (TNF) inhibitors have been the primary biologic option for treatment induction and maintenance of moderate to severe IBD. Although TNF inhibitors have significantly improved outcomes for some patients, approximately one-third are primary nonresponders. Additionally, among patients who initially respond to infliximab, for example, approximately 40% with have disease that will become refractory over time. The annual risk of loss of response is 13% with infliximab and 20% with adalimumab.6,7 The optimal management of patients with CD that has failed treatment with TNF inhibitors remains clinically challenging. Poor outcomes for some patients treated with TNF inhibitors and limited options following failure of treatment with TNF inhibitors have created opportunities for investigating new treatment options with unique mechanisms of action.

In the past several years, new treatments in different therapeutic classes have been developed and approved for clinical use (Table). Mechanistically, approved agents inhibit various inflammatory cytokines, the Janus kinase signal transducer and activator of the transcription pathway, or inhibit leukocyte and lymphocyte trafficking to the gut.6 Despite progress, approved treatment options remain limited for patients with CD that is refractory to treatment with TNF inhibitors or for whom treatment with TNF inhibitors is contraindicated. Approved agents supported by phase 3 randomized trials are ustekinumab, an anticytokine agent targeting the interleukin (IL)-23 and T-helper cell-17 (Th-17) pathways; natalizumab; and vedolizumab, an anti-cell adhesion therapy.8-13 However, natalizumab is associated with increased risk for progressive multifocal leukoencephalopathy, and vedolizumab has a limited and delayed response in patients previously treated with TNF inhibitors.6



What is the rationale for targeted therapy in CD?

Innate and adaptive immunity are involved in IBD pathophysiology; however, the underlying trigger for adaptive immunity in ulcerative colitis differs from that of CD. The adaptive immune response in CD is driven by Th1 cells induced by IL-12, resulting in the production of proinflammatory cytokines, including interferon-γ and TNF. In contrast, ulcerative colitis is driven by Th2 cells with an increased release of IL-5, IL-6, IL-13, and TNF.6 These differences between CD and UC are essential to therapeutic development and suggest that a good understanding of the disease mechanism is essential for selecting appropriate treatment for personalized disease management.

A variant of the gene encoding a subunit of the IL-23 receptor, a cytokine involved in the differentiation of Th-17 cells, is significantly associated with CD. IL-23 shares 1 subunit of p40 with IL-12; therefore, the IL-12/IL-23/Th-17 axis of the innate immune system is pivotal to CD pathogenesis.6 Agents that target IL-23 and Th-17 appear to preferentially benefit patients with prior exposure to, and failure or intolerance of, TNF inhibitors.5 Speculation is that responders might represent a population in whom CD is driven by IL-12/IL-23/Th-17-dependent immunologic pathways and less by the TNF-independent pathway. It has also been speculated that blockade of TNF might lead to emergence of proinflammatory mechanisms that could be dependent on IL-12/IL-23/Th-17 pathways.6

It should be noted that, among the agents investigated that target the IL-12/IL-23/Th-17 pathways, only ustekinumab is approved for clinical use.9 Risankizumab, brazikumab, and mirikizumab are in late-phase clinical development (Table).14-16

Why target IL-12/IL-23/Th-17 pathways with ustekinumab to treat CD?

Ustekinumab is a nonselective immunoglobulin G1 humanized monoclonal antibody targeting the shared p40 subunit of IL-12 and IL-23, resulting in the blockade of IL-12- and IL-23-mediated downstream cell signaling, gene activation, and cytokine production.17,18 Ustekinumab binds to IL-12 and IL-23 and equally neutralizes associated T-cell activation, differentiation, and the subsequent cytokine cascade of inflammation seen in CD. However, most initial studies of ustekinumab were primarily with psoriasis and psoriatic arthritis patient populations in which only 3% of the patients had IBD.18

The ongoing UNIFI trial (Clinicaltrials.gov Identifier: NCT02407236) is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study explicitly evaluating the safety and efficacy of ustekinumab for induction and maintenance of clinical remission in patients with moderately to severely active ulcerative colitis. More patients receiving intravenous ustekinumab at a dose of 130 mg (or 6 mg/kg) reached clinical remission by week 8 compared with placebo (15.6% vs 5.3%; P <.001). Estimated study completion date is November 2021.19,20


Ustekinumab Adverse Effects
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Adverse effects most commonly reported include nasopharyngitis, upper respiratory tract infection, headache, and fatigue.

The efficacy of ustekinumab was demonstrated in a retrospective analysis of 122 patients with active CD that failed to respond to treatment with at least 1 TNF inhibitor; failure or intolerance to thiopurines or methotrexate was reported in 98% of participants. These patients received at least 1 subcutaneous injection of ustekinumab between March 2011 and December 2014, with a minimum follow-up of 3 months. The study’s primary outcome included improvement in CD-related symptoms, which was defined as (1) reduction in symptoms and biochemical markers of CD and (2) complete weaning from corticosteroids without surgery or reintroduction of immunosuppressants. The primary outcome was achieved in 79 of 122 (65%) patients. Moreover, of the 19 patients on corticosteroids, 7 (37%) were able to discontinue them completely and 21% were able to partially discontinue the therapy. This study provided evidence of the effectiveness of ustekinumab in patients with CD and supported the concept of personalized medicine, in that ustekinumab targeted patients with CD that had failed to respond to treatment with TNF inhibitors.5

Two pivotal phase 3 trials, UNITI-1 (ClinicalTrials.gov Identifier: NCT01369329) and UNITI-2 (ClinicalTrials.gov Identifier: NCT01369342), demonstrated the clinical efficacy and safety of ustekinumab in TNF inhibitor-naive and TNF inhibitor-exposed patients:

  • UNITI-1 included patients who met the criteria for primary or secondary nonresponse to treatment with a TNF inhibitor or had unacceptable adverse effects; and
  • UNITI-2 included patients in whom conventional therapy had failed or who had unacceptable adverse effects.8

Ustekinumab was approved in 2017 by the US Food and Drug Administration and the European Medicines Agency for the treatment of moderately to severely active CD in (1) patients for whom conventional therapy with corticosteroids or other immunomodulators failed or they demonstrated intolerance and (2) patients for whom therapy with 1 or more TNFi failed or they demonstrated intolerance.9,21
 
A subset of patients with CD do not respond to ustekinumab at the standard dosage of 90 mg every 8 weeks. However, a retrospective study that compared 506 patients who received ustekinumab 90 mg every 8 weeks and 110 patients who received ustekinumab 90 mg every 8 weeks but then shortened that interval to every 4 weeks found that the shortened interval was safe and effective in improving clinical outcomes in patients with an inadequate response. After shortening the dosing interval, 28% of patients achieved clinical remission, 22% had a normal C-reactive protein level (<5 mg/dL), 50% had a reduced fecal calprotectin level, and 36% achieved endoscopic remission.22 This study suggests that patients with an inadequate response to the standard ustekinumab dosage might benefit from shortening the dosing interval.
The long-term safety, efficacy, and immunogenicity of ustekinumab as maintenance therapy in patients with CD was evaluated over 3 years in the IM-UNITI study (ClinicalTrials.gov Identifier: NCT01369355) and in the long-term extension study over 5 years.23 The study found that the cumulative dose of ustekinumab maintained clinical response and remission over 5 years in patients with CD. The study results also suggest that concomitant immunosuppression in patients treated with ustekinumab is unnecessary. At 5 years, most patients in remission were not receiving corticosteroids.23 Ustekinumab is the treatment of choice for patients with CD refractory to treatment with TNF  inhibitors.

References

 
1. GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17-30. doi:10.1016/S2468-1253(19)30333-4

2. Inflammatory bowel disease prevalence in the United States. Centers for Disease Control and Prevention. Updated August 11, 2020. Accessed June 21, 2021. www.cdc.gov/ibd/data-statistics.htm

3. Behzadi P, Behzadi E, Ranjbar R. The incidence and prevalence of Crohn’s disease in global scale. SOJ Immunology. 2015;3(2):1-6.  doi:10.15226/soji/3/2/00125

4 Veauthier B, Hornecker JR. Crohn’s disease: diagnosis and management. Am Fam Physician. 2018;98(11):661-669.

5. Rivera-Nieves J, Bamias G. Anti-interleukin-12/23 blockade offers novel therapeutic opportunities for the “difficult” patient with Crohn’s disease. Gastroenterology. 2016;150(5):1237-1239. doi:10.1053/j.gastro.2016.03.023

6. Schreiner P, Neurath MF, Ng SC, et al. Mechanism-based treatment strategies for IBD: cytokines, cell adhesion molecules, JAK inhibitors, gut flora, and more. Inflamm Intest Dis. 2019;4(3):79-96. doi:10.1159/000500721

7. Roda G, Jharap B, Neeraj N, Colombel J-F. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7(1):e135. doi:10.1038/ctg.2015.63

8. Feagan BG, Sandborn WJ, Gasink C, et al; UNITI–IM-UNITI Study Group. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946-1960. doi:10.1056/NEJMoa1602773

9. Stelara (ustekinumab). Prescribing information. Janssen Biotech, Inc.; December 2020. Accessed June 21, 2021. www.janssenlabels.com/package-insert/product-monograph/prescribing-information/STELARA-pi.pdf

10. Sandborn WJ, Colombel JF, Enns R, et al; International Efficacy of Natalizumab as Active Crohn’s Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353(18):1912-1925. doi:10.1056/NEJMoa043335

11. Tysabri. Prescribing information. Biogen; 2020. Accessed June 21, 2021. www.tysabri.com/content/dam/commercial/tysabri/pat/en_us/pdf/tysabri_prescribing_information.pdf

12. Sandborn WJ, Feagan BG, Rutgeerts P, et al; GEMINI 2 Study Group. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711-721. doi:10.1056/NEJMoa1215739

13. Entyvio. Prescribing information. Takeda Pharmaceuticals; 2014. Accessed June 21, 2021. www.accessdata.fda.gov/drugsatfda_docs/label/2014/125476s000lbl.pdf

14. Phase 3 maintenance results show patients with Crohn’s disease receiving risankizumab (SKYRIZI®) achieved endoscopic response and clinical remission at one year. News release. June 2, 2021. Accessed June 14, 2021. https://news.abbvie.com/news/press-releases/phase-3-maintenance-results-show-patients-with-crohns-disease-receiving-risankizumab-skyrizi-achieved-endoscopic-response-and-clinical-remission-at-one-year.htm
 
15. AstraZeneca to recover the global rights to brazikumab (MEDI2070) from Allergan. Press release. January 27, 2020. Accessed June 21, 2021. https://www.astrazeneca.com/media-centre/press-releases/2020/astrazeneca-to-recover-the-global-rights-to-brazikumab-medi2070-from-allergan-27012020.html

16. A study of mirikizumab (LY3074828) in participants with Crohn’s disease (VIVID-1). ClinicalTrials.gov Identifier: NCT03926130. Updated June 18, 2021. Accessed June 14, 2021. https://clinicaltrials.gov/ct2/show/NCT03926130

17. Aggeletopoulou I, Assimakopoulos SF, Konstantakis C, Triantos C. Interleukin 12/interleukin 23 pathway: biological basis and therapeutic effect in patients with Crohn’s disease. World J Gastroenterol.;24(36):4093-4103. doi:10.3748/wjg.v24.i36.4093

18. Verstockt B, Ferrante M, Vermeire S, Van Assche G. New treatment options for inflammatory bowel diseases. J Gastroenterol. 2018;53(5):585-590. doi:10.1007/s00535-018-1449-z

19. A study to evaluate the safety and efficacy of ustekinumab induction and maintenance therapy in participants with moderately to severely active ulcerative colitis (UNIFI). ClinicalTrials.gov Identifier: NCT02407236. Updated June 9, 2021. Accessed June 21, 2021. https://clinicaltrials.gov/ct2/show/NCT02407236

20. Sands BE, Sandborn WJ, Panaccione R, et al; UNIFI Study Group. Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2019;391:1201-1214. doi:10.1056/NEJMoa1900750

21. European Medicines Agency. Stelara. Updated April 5, 2021. Accessed June 21, 2021. www.ema.europa.eu/en/medicines/human/EPAR/stelara

22. Ollech JE, Normatov I, Peleg N, et al. Effectiveness of ustekinumab dose escalation in patients with Crohn’s disease. Clin Gastroenterol Hepatol. 2021;19(1):104-110. doi:10.1016/j.cgh.2020.02.035

23. Sandborn WJ, Rebuck R, Wang Y, et al. Five-year efficacy and safety of ustekinumab treatment in Crohn’s disease: the IM-UNITI trial. Clin Gastroenterol Hepatol. 2021:S1542-3565(21)00203-2. Published online February 19, 2021. doi:10.1016/j.cgh.2021.02.025

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Reviewed June 2021