Introduction

Histologic inflammation persists in up to 1/4 of patients (pts) with Crohn’s Disease (CD) despite endoscopic mucosal healing. Responsiveness of histologic inflammation and of combined endoscopic-histologic endpoints to treatment are evolving measures of disease activity in CD. Mirikizumab (MIRI) increased histologic response (H-Res) and remission (H-Rem) relative to placebo (PBO) in the Phase 2 SERENITY trial.¹

Aims & Methods

To evaluate the impact of MIRI and ustekinumab (UST) on H-Res and H-Rem and combined endoscopic-histologic response (EH-Res) and remission (EH-Rem) in all pts, pts with prior biologic failure (BF), pts without prior BF in moderately to severely active CD, in the randomized, double-blind, double-dummy, treat-through Phase 3 VIVID-1 trial (NCT03926130). Two biopsy specimens from each of 5 intestinal segments (1 ileal and 4 colonic) were obtained from the edge of the ulcers, or the most inflamed mucosa from randomized pts at screening, and weeks (W)12, and 52. Criteria for H-Res were the absence of epithelial neutrophils and epithelial damage, erosions and ulceration or ≥50% decrease in either the active Robarts Histopathology Index or the active Global Histologic Disease Activity Score. H-Rem was defined as complete absence of mucosal neutrophils (in epithelium and lamina propria), and no epithelial damage, erosions and ulcers; these criteria had to be met in all biopsy specimens. Endoscopic response was defined as ≥50% improvement from baseline in Simple Endoscopic Score for CD (SES-CD). Endoscopic remission was defined as SES-CD total score ≤4 and ≥2-point reduction from baseline and no subscore >1 in any individual variable.

Results

At W52, nominally significant differences between MIRI and UST were observed in achieving H-Res in all pts (58.2% vs 48.8%; p=.007 and in BF pts (56.5% vs 41.3%; p=.006). For EH-Res, differences of MIRI vs UST were numerically greater but not statistically significant in all pts (41.1% vs 34.4%; p=.063) but were nominally significant among BF pts (39.6% vs 27.8%; p=.023). While numerical differences between MIRI and UST were observed in H-Rem and EH-Rem in all pts (H-Rem: 30.2% vs 28.9%; p=.685; EH-Rem: 17.2% vs 14.8%; p=.363) and in BF pts (H-Rem: 24.3% vs 19.8%; p=.365; EH-Rem: 13.3% vs 8.7%; p=.237), no significant differences were observed in these endpoints(Table).

Conclusion

Using strict definitions, all histology-based endpoints were achieved by MIRI versus PBO. For comparison versus UST, MIRI also showed nominal statistical difference for H-Res, which was prespecified and is considered the most sensitive to change, particularly driven by BF pts. The implication of these results on clinical endpoints and long-term outcomes, including hospitalization rates and surgeries, requires further evaluation.

References

1. Magro F, et al. Clin Gastroenterol Hepatol. 2023:S1542-3565(23)00948-5.

Disclosure

• V. Jairath received consulting/advisory board fees: AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Endpoint Health, Enthera, Ferring Pharmaceuticals, Flagship Pioneering, Fresenius Kabi, Galapagos NV, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead Sciences, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Biosciences, Protagonist Therapeutics, Reistone Biopharma, Roche, Roivant Sciences, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, TD Securities, Teva, Topivert, Ventyx Biosciences, and Vividion Therapeutics; and speaker’s fees: AbbVie, Bristol Myers Squibb, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Janssen, Pfizer, Shire, and Takeda
• F. Magro speaker: AbbVie, Arena, Biogen, Bristol Myers Squibb, Eli Lilly and Company, Falk, Ferring Pharmaceuticals, Hospira, Janssen, Laboratórios Vitoria, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, UCB, and Vifor
• G. De Hertogh received fees for clinical trial activities with Centocor Inc; and received consultancy fees: Eli Lilly and Company and MRM Health
• B. Feagan was a consultant: AbbVie, AbolerIS Pharma, Agomab Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport, Arena Pharmaceuticals, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celgene/BMS, Celsius Therapeutics, Connect BioPharma, Cytoki Pharma, Disc Medicine, Duality, EcoR1, Eli Lilly and Company, Equillium, Ermium Therapeutics, First Wave BioPharma, First Word Group, Galapagos NV, Galen Atlantica, Genentech/Roche, Gilead Sciences, Gossamer Pharma, GlaxoSmithKline, Hinge Bio, Hot Spot Therapeutics, InDex Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco, Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium Pharmaceuticals, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist Therapeutics, PTM Therapeutics, Q32 Bio, Rebiotix, Redx Pharma, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHsquared, Viatris, Ysios, YSOPIA Bioscience, and Zealand Pharma; was on the speaker’s bureau: AbbVie, Janssen, and Takeda; member of the Scientific Advisory Board, DSMB for: AbbVie, Amgen, AMT, AnaptysBio, Axio Research, Boehringer Ingelheim, Celgene/BMS, Ecor1Capital, Eli Lilly and Company, Genentech/Roche, GlaxoSmithKline, InDex Pharma, Janssen, MiroBio, Morphic, Origo BioPharma, Pfizer, Progenity, Prometheus, Redx Pharma, Sanofi, Takeda, Tillotts Pharma, and Teva; stock shareholder of: Gossamer Pharma; and employee as Senior Scientific Director of: Western University and Alimentiv
• N. Harpaz advisory board member and/or consultant: AbbVie, Bristol Meyers Squibb, Eli Lilly and Company, and PathAI Inc
• T. Hisamatsu received lecture fees: AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda; received honoraria as an advisory board member or consultant: AbbVie, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Pfizer, and Takeda; and received pharmaceutical/research grants from: AbbVie, Alfresa Pharma, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nichi-lko Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical
• G. D’Haens advisor: AbbVie, Agomab Therapeutics, Alimentiv, AstraZeneca, Biora, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Exeliom Biosciences, Galapagos NV, Genentech/Hoffmann-La Roche, GlaxoSmithKline, Immunic Therapeutics, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Protagonist Therapeutics, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Takeda, Tillotts Pharma AG, Ventyx; received speaker fees: AbbVie, Johnson & Johnson, Takeda, Pfizer, Tillotts Pharma AG
• R. Pai received consulting fees: Alimentiv Inc, Allergan, and BRACCO
• Z. Lin, N. Morris, M. Protic, E. Hon, C. Owen, R. Escobar are employees and shareholders: Eli Lilly and Company
• W. Reinisch received lecture and consulting fees from and/or served as an advisory board member: AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix Pharmaceuticals, Takeda, UCB Pharma, and Vifor Pharma

Introduction

Postoperative recurrence is common in Crohn's disease following ileocecal resection, with varying management strategies employed. This study aimed to compare the efficacy of prophylactic approach (starting thiopurines or biological therapy within 6 months from the surgery) versus reactive one (starting biological therapy after evidence of disease reactivation) in preventing postoperative recurrence.

Aims & Methods

This retrospective, multicenter study included 895 adult patients who underwent ileocecal resection for Crohn's disease across 13 Italian centers (prophylactic strategy: n=196; reactive strategy: n=699). Patients were classified as high-risk (≥1 risk factor: active smoking, prior intestinal resection, penetrating disease, perianal disease, or large resection ≥50 cm) or low-risk. The primary outcome was endoscopic recurrence (Rutgeerts' score ≥i2a) at 6-12 months post-surgery. Secondary outcomes included clinical, biochemical, and radiological recurrence at various time points, as well as long-term outcomes including need for repeat surgery.

Results

The prophylactic biologic therapy group demonstrated significantly lower rates of endoscopic recurrence at 6-12 months compared to the reactive approach (51.54% vs. 64.83%, p=0.007). After adjusting for confounders, including age at surgery and previous biologic exposure, a reactive approach was associated with increased odds of endoscopic recurrence (OR 1.893, 95% CI: 1.225-2.926, p=0.004). The prophylactic strategy also showed lower rates of clinical recurrence (23.08% vs. 36.36%, p=0.002), biochemical recurrence (33.81% vs. 48.89%, p=0.004), and severe endoscopic recurrence (22.31% vs. 32.55%, p=0.028) at 6-12 months. In high-risk patients with a single risk factor, prophylaxis significantly reduced endoscopic recurrence (49.06% vs. 65.75%, p=0.033) and surgical recurrence (2.56% vs. 11.58%, p=0.017). For patients with multiple risk factors, benefits were mainly observed in clinical (29.87% vs. 45.77%, p=0.022) and biochemical recurrence (37.88% vs. 56.32%, p=0.024). In low-risk patients, prophylaxis primarily reduced severe endoscopic recurrence (10.52% vs. 34.48%, p=0.037), but not other outcomes. However, these benefits diminished over time, with no significant differences in all outcomes at 15-36 months or in long-term surgical recurrence rates as compared to patients undergoing the reactive approach in all groups (p=0.438). No significant difference was observed between the two approaches regarding the need for endoscopic dilation during follow-up (p=0.301).

Table 1: Differences in outcomes at 6-12 months between a proactive and reactive strategy approach. Abbreviations: CD: Crohn's Disease, FC: Fecal Calprotectin, HBI: Harvey-Bradshaw Index

Conclusion

A prophylactic strategy significantly reduces short-term postoperative recurrence in Crohn's disease patients following ileocecal resection, with particular benefit in high-risk patients with a single risk factor. However, the protective effects appear to diminish over time. Further research is needed to refine predictive models and validate interventions targeting high-risk populations for sustained benefits.