Introduction

Icotrokinra (JNJ-2113) is a first-in-class targeted oral peptide that selectively blocks IL-23 receptor (IL-23R) activation. We evaluated the efficacy and safety of icotrokinra in adult participants with moderately to severely active ulcerative colitis (UC) in a phase 2b, randomized, double-blind, placebo-controlled, treat-through, 28-week, dose-ranging study (ANTHEM-UC).

Aims & Methods

Eligible participants with moderately to severely active UC defined as a modified Mayo score (mMS) of 5–9 (inclusive) and a Mayo endoscopy subscore (MES) ≥2 and history of inadequate response or intolerance (IR) to TNFα blockers, vedolizumab, ustekinumab, JAK inhibitors, or S1P modulators (BIO/JAKi/S1Pi-IR) or IR to corticosteroids (CS), azathioprine, or mercaptopurine were randomized 1:1:1:1 to once-daily (qd) oral icotrokinra 100 mg, 200 mg, 400 mg, or placebo (PBO). At randomization, participants were stratified by BIO/JAKi/S1Pi-IR status (yes/no) and MES (2 or 3).
The primary endpoint was clinical response at Week 12 (W12); secondary endpoints were clinical remission, symptomatic remission, endoscopic improvement, and histologic-endoscopic mucosal improvement (HEMI) at W12. The study was powered to detect a treatment difference between icotrokinra 400 mg and PBO for the primary endpoint; it was not powered for secondary endpoints.

Results

Overall, 252 participants were randomized and received study medication (primary analysis population: mean age, 41.6 y; male 58.3%; mean UC duration, 7.8 y; mean mMS, 6.63; mMS > 7 [severe], 31.9%; MES = 3 [severe], 58.7%; baseline CS use, 37.3%; BIO/JAKi/S1Pi-IR, 43.3%). Baseline demographic and disease characteristics were generally similar across groups.
All icotrokinra doses met the primary endpoint, demonstrating superiority to PBO for clinical response at W12 (Table). Relative to PBO, significantly greater proportions of participants achieved clinical remission, symptomatic remission, and endoscopic improvement at W12 in the icotrokinra 400 mg group, with clinically meaningful differences for HEMI at W12 in the icotrokinra 400 mg group. Clinically meaningful differences were observed for icotrokinra 100 mg and 200 mg vs PBO at W12 across secondary endpoints. All icotrokinra doses demonstrated separation from PBO for symptomatic remission as early as W4.
Across the PBO and 100 mg, 200 mg, and 400 mg icotrokinra groups, respectively, similar proportions of participants reported ≥1 AEs (50.8%, 50.0%, 45.2%, 46.0%), SAEs (4.8%, 0%, 3.2%, 1.6%), serious infections (1.6%, 0%, 0%, 0%), and AEs leading to discontinuation of study agent (7.9%, 0%, 6.5%, 1.6%) through W12. No opportunistic infections, tuberculosis, malignancies, clinically important hepatic disorders, MACE, or deaths were reported in icotrokinra treatment groups through W12.

Conclusion

Icotrokinra, the first-in-class targeted oral peptide that selectively blocks IL-23R activation, demonstrated efficacy and a favorable safety profile in participants with moderately to severely active UC.

Disclosure

Maria T. Abreu: consultant/advisory board member for AbbVie, Arena Pharmaceuticals (now Pfizer), Bristol Myers Squibb, Celsius Therapeutics, Gilead, Johnson & Johnson, Lilly, Pfizer, Prometheus Biosciences, UCB; lecture fees from Alimentiv, Johnson & Johnson, Prime, WebMD Global LLC
Britta Siegmund: consultant for AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Falk, Galapagos, Gilead, Johnson & Johnson, Landos, Materia Prima, PredictImmune, Pfizer, Takeda; speaker fees from AbbVie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, MSD, Ferring, Galapagos, Johnson & Johnson, Pfizer, Takeda; grant from Pfizer
Minhu Chen: research grants and steering committee advisor for Johnson & Johnson; lecture fees from AbbVie, China Medical System Holding Limited, Johnson & Johnson, Takeda
Karen Chachu: advisory board for Johnson & Johnson; consultant for OptumRx
Edouard Louis: educational and research grants from AbbVie, Celltrion, Falk, Fresenius-Kabi, Johnson & Johnson, Pfizer, Takeda; speaker fees from AbbVie, BMS, Celltrion, Ferring, Fresenius-Kabi, Galapagos, Johnson & Johnson, Pfizer, Takeda; advisory board for AbbVie, BMS, Celgene, Eli Lilly, Ferring, Johnson & Johnson, Pfizer, Takeda; consultant for AbbVie, Aboleris, Biokuris, Thabor
Katsuyoshi Matsuoka: speaker fees from Johnson & Johnson, Abbvie, Takeda, Pfizer, Gilead, Eli Lilly, Mitsubishi Tanabe Pharma, EA Pharma, Mochida, Kyorin, Zeria, Nippon Kayaku; research support from AbbVie, Mitsubishi Tanabe Pharma, EA Pharma, Mochida, Kyorin, Zeria, Nippon Kayaku, JIMRO; advisor to Johnson & Johnson, AbbVie, Takeda, Pfizer, Gilead, Eli Lilly, EA Pharma, Mochida, Kyorin, Bristol Myers Squibb, Celltrion Healthcare
Jimmy Limdi: speaker/consultancy fees from AbbVie, Abivax, Arena, BioHit, Celltrion, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MSD, Pfizer, Takeda; research support from Galapagos, Takeda
Grazyna Rydzewska: speaker and consultant fees from AbbVie, AlfaSigma, AstraZeneca, Bayer, Biocodex, Bristol Myers Squibb, Ferring, Johnson & Johnson, Lilly, PRO.MED.Pl, Recordati, Sanprobi, SOBI, Takeda; travel/accomodation meeting expenses from AbbVie, Ferring, Takeda
Edward V. Loftus, Jr.: consulting for AbbVie, Abivax, Astellas, Avalo Therapeutics, Biocon, Bristol-Myers Squibb, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, Iota Biosciences, Iterative Health, Johnson & Johnson, Merck, Morphic, Ono, Takeda, TR1X Bio; research support from AbbVie, Genentech, Gilead, Gossamer Bio, Johnson & Johnson, Merck, Takeda; shareowner of Exact Sciences, Moderna.
Vipul Jairath: consulting/advisory board fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Johnson & Johnson, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; speaker fees from AbbVie, Ferring, Bristol Myers Squibb, Fresenius Kabi, Galapagos, Johnson & Johnson, Pfizer, Shire, Takeda
Lindsey Surace, Ngozi Erondu, Edmund Arthur, Nicole Houck, Mary Ellen Frustaci, Bin Zou: employee and shareholder of Johnson & Johnson

Introduction

Immune checkpoint inhibitor (ICI) mediated enterocolitis (IMC) may lead to treatment discontinuation. Corticosteroids for IMC is associated with serious side effects and might affect cancer progression in addition to preclude continued ICI treatment. We hypothesized that vedolizumab, a gut selective α4β7 integrin inhibitor, is effective as a first-line treatment and investigated whether vedolizumab reduces corticosteroid exposure and facilitate ICI resumption.

Aims & Methods

We conducted a single center, open-label, explorative phase 2 trial including patients treated with ICI who developed IMC. Patients were randomized 1:1 ratio to receive vedolizumab (300 mg) or standard treatment with corticosteroids, with infliximab used as recue therapy for corticosteroid failure. The primary outcome was cumulative corticosteroid dose at week 30. Key secondary outcomes included cumulative corticosteroid dose at week 10, corticosteroid free remission at week 10 and ICI resumption rates.

Results

Twenty-two patients received vedolizumab, and 19 patients received standard treatment. At week 10, the mean cumulative corticosteroid use was significantly lower in the vedolizumab arm (1157 mg vs. 2207 mg). By week 30, the mean corticosteroid use remained lower but not statistically significant (1378 mg vs. 2390 mg, estimated difference 1012 mg, 95% CI -229 to 2253, p=0.107), Among patients with less severe IMC, who did not need corticosteroids during screening, vedolizumab-treated patients used in average 1729 mg less corticosteroid (95% CI 631 to 2827). Corticosteroid-free remission at weeks 2 and 10 was more common with vedolizumab. Seven patients (33.3%) in the vedolizumab group resumed with ICI compared to three (16.7%) in the standard arm. In patients with severe colitis, who required upfront corticosteroid treatment, a trend towards longer hospitalization in the vedolizumab arm was observed.

Conclusion

For patients with less severe colitis, not needing corticosteroids during screening, vedolizumab may be a viable corticosteroid-sparing option, enabling faster remission and ICI resumption.

Disclosure

The study was funded by Aage og Johanne Louis-Hansens Fond, National Research grants. Takeda Pharma provided the study drug vedolizumab.

Introduction

Barrier healing (BH) has emerged as a novel treatment target in Inflammatory Bowel disease (IBD). Persistence of barrier impairment despite endoscopic and histological remission has been associated with worse long-term outcomes. However, accurate real-time assessment of intestinal barriers remains challenging in clinical practice. This study explores the role of advanced endoscopy (ultra-high magnification endocytoscopy [ECS] and confocal laser endomicroscopy [CLE]) for real-time, in vivo, structural and functional assessment of epithelial and vascular intestinal barrier. Further, we aim to investigate their correlation with automated barrier protein expression and clinical outcomes in IBD.

Aims & Methods

IBD patients undergoing endoscopic evaluation and healthy controls (HC) were recruited from two tertiary university centres.
The intestinal mucosa was assessed with ECS or CLE by novel scoring systems including epithelial and vascular features. BH was defined as ECS score ≤1 or CLE score ≤4, with preserved villi/crypt architecture, normal vessels, and, for CLE, absence of fluorescein leakage.
Biopsies were collected from both inflamed and non-inflamed areas. Epithelial (ZO-1, Claudin-2, E-cadherin) and vascular (PV-1 and CD-31) barrier markers were analysed through confocal microscopy, and their mean expression was automatically quantified using QuPath (v0.5.1). A biopsy-wise analysis assessed the correlation between endoscopic and histopathological evaluation. Moreover, occurrence of clinical outcomes at 6-month follow-up according to imaging-detected barrier impairment was evaluated.

Results

A total of 74 IBD patients (39 Crohn’s disease [CD], 35 Ulcerative colitis [UC]) and 9 HC) were considered. 46% (34/74) and 42% (30/74) IBD patients were in endoscopic and histological remission, respectively, while advanced imaging-defined BH was present in 24.3% (18/74) patients (Table 1). Barrier impairment was significantly associated with clinical outcomes at 6-month follow-up (p<0.01).
Mean expression of Claudin-2 was significantly higher in UC with ECS-based barrier impairment (85.5 vs 175.1, p 0.02), while PV1 expression was elevated in CD with CLE-based barrier dysfunction (362.1 vs 442.2, p 0.1). Significant correlations were found between ECS/CLE scores and epithelial and vascular barrier proteins.
In UC, Claudin-2 showed a moderate correlation with altered crypt architecture, goblet cell depletion and ECS total score (r 0.5), while PV-1 was moderately associated with altered vascular pattern and ECS total score (r -0.4).
In CD, Claudin-2 demonstrated a moderate correlation with crypt distortion, goblet cell depletion and total CLE scores (r 0.5), while PV-1 moderately correlated with fluorescein leakage, altered vessel architecture and total CLE score (r 0.4).

Conclusion

pCLE and ECS enable real-time intestinal barrier assessment in IBD, showing good correlation with epithelial and vascular barrier proteins and predicting clinical outcomes. This approach shows promise for targeting BH, guiding early and long-term disease management, and enabling flare-up prediction.