Treatment Updates on Inflammatory Bowel Disease

Educational Objectives

The goal of this program is to improve management of inflammatory bowel disease (IBD). After hearing and assimilating this program, the clinician will be better able to:

1. Select patients with IBD who are likely to benefit from use of recently approved medical therapies.
2. Compare the benefits and adverse effect profiles of medical therapies recently approved for patients with IBD.

Summary

Crohn Disease

Ustekinumab vs selective interleukin (IL)-23 inhibitors: ustekinumab blocks the p40 protein subunit, which is shared by IL-12 and IL-23; selective IL-23 inhibitors target the p19 subunit; psoriasis data suggest that selective IL-23 inhibition has a greater efficacy and more selective toxicity (although ustekinumab also has a favorable safety profile)

Risankizumab: Feagan et al (2017), which mostly included patients who had previously received anti-tumor necrosis factor (TNF) agents, found a clinically significant difference in rate of clinical remission between risankizumab and placebo (36% vs 15% at 12 wk); efficacy was observed in phase 3 trials independent of prior exposure to anti-TNF therapy

Maintenance trials: in general, differences between patients who continue vs those who withdraw from therapy take longer to be observed when the drug has a long carryover effect from induction therapy

Biomarkers: C reactive protein (CRP) and fecal calprotectin (FC) levels decreased from induction to the start of the maintenance period (12 wk); patients who withdrew from therapy had increases in FC and CRP over time

Endoscopic improvement: even with rigorous definitions of endoscopic remission, significant improvements over placebo were observed in patients with or without prior anti-TNF drug experience

Practical considerations: a slow injector device may be helpful for patients with a fear of needles; much is unknown about transitioning patients from the intravenous (IV) induction period to the subcutaneous maintenance period; monitor laboratory values (especially liver enzymes); watch for infusion reactions and infections (although the safety profile is favorable overall)

Guselkumab: is an IL-23 selective inhibitor; Sandborn et al (2022) included a ustekinumab reference arm (but was not powered to detect a difference between guselkumab and ustekinumab); a greater decrease in Crohn Disease Activity Index scores from baseline was observed in the guselkumab groups; rates of clinical remission and clinical response were substantially higher in the guselkumab groups compared with placebo, with a large proportion of patients in the study having prior exposure to biologic therapy; significant differences in endoscopic outcomes were observed between placebo and drug-treated groups

Ulcerative Colitis

Mirikizumab: the phase 3 LUCENT-1 trial compared mirikizumab with placebo as induction therapy; a large proportion of participants were refractory to biologic agents or tofacitinib; clinical remission — observed in 24% of the mirikizumab group and 13% of the placebo group; significant improvements were observed in patients with or without exposure to biologics (although difference between groups was smaller with prior biologic exposure); endoscopic and histologic endpoints — mirikizumab was significantly better than placebo at 12 wk; proportion of patients with Mayo Endoscopic Subscore of 0 or 1 and rate of histologic-endoscopic improvement were significantly greater with mirikizumab; symptom improvement was observed as early as 2 wk with mirikizumab; improvement in a novel bowel Urgency Numeric Rating Scale was significantly greater with mirikizumab and observed as early as 2 wk; maintenance phase — response during maintenance was ≈25% greater than with placebo among patients who responded to mirikizumab during induction

Ozanimod: internalizes the sphingosine 1-phosphate receptor inside of the lymphocyte; a significant difference in rates of clinical remission (18% vs 6% with placebo) and clinical response were observed with ozanimod; rates of endoscopic improvement (27% vs≈12%) and mucosal healing was significantly greater with ozanimod; differences were maintained for 1 yr; a clinical response can be seen by 2 wk, but clinical remission takes longer (≈4 wk); stratification by prior anti-TNF drug use — the differences from placebo were ≈5% and ≈15% for patients with and without prior anti-TNF drug exposure, respectively, suggesting that ozanimod is less effective for patients with prior exposure to anti-TNF agents; adverse effects — include bradycardia, macular edema, and hypertensive crisis, but these are rare

Take-home messages: ozanimod is useful for patients with moderate to severe UC as first-line therapy, but perhaps not for those who have received biologic therapy; it is an oral drug and can be used after mesalamine for some patients

Contraindications and cautions: use with caution in patients with recent myocardial infarction, arrhythmia, and severe sleep apnea; obtain baseline laboratory testing, electrocardiography, and ophthalmology examination (if the patient has a history of macular edema or uveitis)

Tofacitinib: tofacitinib, which has been approved for UC, is a nonselective Janus kinase (JAK) inhibitor (blocks JAK1, JAK2, and JAK3); blocking these cytokines and potentially pro-inflammatory signals that lead to inflammation can improve efficacy, but multiple safety concerns must also be considered; more selective JAK inhibition may theoretically improve the safety profile

Upadacitinib (UPA): JAK inhibitor approved for UC; induction dosing — although a large proportion of patients had been exposed to anti-TNFs or other biologic agents, a large difference in response was observed between placebo and UPA; there was a substantial separation at 2 wk, and the endpoint was met at wk 8 for clinical parameters; a considerable improvement in endoscopic remission was also observed; large differences in histologic, histologic-endoscopic, and mucosal healing were observed between drug and placebo

Maintenance dosing: showed maintenance of response over time; the label recommends using the lowest effective dose (15 mg); for more severe or refractory disease, 30 mg can be used; UPA 15 mg performed significantly better than placebo, but there is likely an incremental benefit between 15 and 30 mg (≈10% for secondary outcomes); balance safety and efficacy considerations when managing patients with disease that is more refractory to therapy

Clinical use: UPA can be considered for patients with moderate to severe UC with intolerance or loss of response to a TNF inhibitor; use an induction dose of 45 mg for 8 wk and a maintenance dose of 15 or 30 mg; monitor patients at risk for infection; monitor creatine phosphokinase levels with all JAK inhibitors (the clinical implication is unknown); a black box warning for JAK inhibitors discusses thrombosis, major adverse cardiovascular events, and death

Readings

Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials. The Lancet. 2022 June 04;399:10341(2113-2128); D'Haens G, Panaccione R, Baert F, et al. Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet. 2022;399(10340):2015-2030. doi:10.1016/S0140-6736(22)00467-6; Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active ulcerative colitis: Results from the phase 3 LUCENT-1 study. Gastroenterol Hepatol (N Y). 2022 Apr;18(4 Suppl 1):7–8; Feagan BG, Sandborn WJ, D'Haens G, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, double-blind, placebo-controlled phase 2 study. The Lancet. 2017 April;29389:10080(1699-1709); Higashiyama M, Hokari R. New and emerging treatments for inflammatory bowel disease. Digestion. 2023;104:74–81; Horst S, Cross RK. Clinical evaluation of risankizumab in the treatment of adults with moderately to severely active Crohn's disease: patient selection and reported outcomes. Drug Des Devel Ther. 2023;17:273-282. Published 2023 Jan 31. doi:10.2147/DDDT.S379446; Sandborn WJ, D'Haens GR, Reinisch W, et al. Guselkumab for the treatment of Crohn's disease: Induction results from the phase 2 GALAXI-1 study. Gastroenterology. 2022 May;162(6):1650-1664.e8; Sandborn WJ, Feagan BG, D’Haens G, et al. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021;385:1280-1291.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Melmed is a consultant for Abbvie, Arena, Bristol-Myers Squibb, Eli Lilly, Entasis, Ferring, Janssen, Pfizer, Shield Healthcare, Shionogi, Takeda, Prometheus, and Techlab. Members of the planning committee reported nothing relevant to disclose. Dr. Melmed's lecture includes information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Melmed was recorded at New Advances in Inflammatory Bowel Disease 2022, held September 10-11, 2022, in San Diego, CA, and presented by Scripps Health. For information on future CME activities from these speakers, please visit scripps.org. Audio Digest thanks the speakers and Scripps Health for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

GE370801

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.