Introduction

The risk of postoperative recurrence (POR) within 1 year after ileocecal resection (ICR) for Crohn’s disease (CD) remains high. Currently, there is no consensus on how to optimally reduce the risk of endoscopic (e)POR, clinical (c)POR or surgical (s)POR.

Aims & Methods

The PORCSE study aims to evaluate the impact of two strategies: early medical prophylaxis (proactive strategy) versus treatment driven by findings at elective endoscopy 6-12 months after ICR (reactive strategy).
A retrospective, observational, multicentric, superiority study was performed including CD patients undergoing first ICR between 2008-2019. Patients were assigned to cohort 1 if prophylactic biological or immunomodulator therapy was administered early after ICR, or to cohort 2 if no postoperative prophylaxis was started and medical treatment was driven by endoscopic findings 6-12 months after ICR. The primary endpoint was the rate of ePOR evaluated at ileocolonoscopy 6-12 months post ICR and was defined as Rutgeerts score >i1. Secondary endpoints were colonic disease activity at first endoscopy, severe ePOR (Rutgeerts i3-i4), cPOR (symptoms leading to restart of therapy), sPOR (repeated surgery or endoscopic balloon dilatation) and differences between participating centres.
Statistical analyses were performed with SPSS v28. Propensity score matching was used for regression analyses.

Results

In total 346 patients were included from 26 centres in 9 European countries. Of these, 47.4% received prophylactic postoperative treatment before postoperative endoscopy (cohort 1) and 52.6% did not (cohort 2). Strategy selection differed significantly between countries (P=0.024). The proactive strategy was preferred in Spain and Portugal whereas the reactive strategy in Belgium, France and Ireland. Although not statistically significant (P=0.143), the same trend was noticed in postoperative metronidazole use.
Patients in cohort 1 had more refractory disease with more upper GI disease, more bio-experienced patients, more penetrating disease phenotype and longer disease duration prior to surgery. Furthermore, metronidazole was more frequently started postoperatively in the proactive cohort (31.7%vs14.3%, P<0.001).
Bivariate logistic regression analyses showed significantly higher odds for ePOR in the reactive treatment group (OR 1.809, 95%CI 1.03-3.18, P=0.039). Furthermore, univariate analyses showed higher rates of colonic disease activity in the reactive group at elective endoscopy 6-12 months after surgery. No significant difference in severe ePOR was found at first endoscopy (OR 1.285, 95%CI 0.60-2.74, P=0.517). After first endoscopy until end of follow-up, patients in the reactive group had significantly higher odds of clinical POR (OR 3.047, 95%CI 1.53-6.08, P=0.002). Surgical recurrence rates were numerically higher in the reactive group (OR 2.586, 95%CI 0.995-6.72, P=0.051) and Cox proportional hazards regression analysis showed a trend towards protective effect of the proactive approach (HR 2.497, 95%CI 0.97-6,40, P=0.057).

Table 1: Demographics and POR

Conclusion

The retrospective PORCSE study provides evidence to support a proactive approach over a reactive approach in terms of prevention of not only endoscopic but also clinical and surgical postoperative recurrence after first ileocecal resection for Crohn’s disease.

Disclosure

Authors have nothing to disclose related to this project

Introduction

In Parts A and B of the 3-part phase 3 LIBERTY EoE TREET study (NCT03633617), dupilumab 300 mg weekly (DPL qw) vs placebo (PBO) demonstrated significant efficacy and acceptable safety up to 24 weeks in adults and adolescents with eosinophilic esophagitis (EoE). For patients who completed Parts A and B, Part C was an extended active treatment period for 28 weeks with patients receiving treatment up to 52 weeks. We previously reported continued improvements in all aspects of disease up to 52 weeks in DPL patients who completed Part A/C, and that PBO patients from Part A who received DPL in Part C showed similar efficacy. Here we present results from patients who completed Part B and continued to Part C, which assessed efficacy and safety of DPL up to 52 weeks in a larger number of patients.

Aims & Methods

Of 80 DPL qw patients in Part B, 74 continued DPL qw in Part C (DPL/DPL). Of 79 PBO patients in Part B, 37 received DPL qw in Part C (PBO/DPL). Part B co-primary endpoints were proportion of patients achieving peak esophageal intraepithelial eosinophil (eos) count ≤6 eos/high power field (hpf) and absolute change from Part B baseline (BL) in Dysphagia Symptom Score (DSQ) score at Week 24. Secondary endpoints are listed in the Table. In Part C, all endpoints were assessed at Week 52 as secondary endpoints. Safety was also assessed.

Table. Summary of co-primary and secondary endpoints at Weeks 24 (Part B) and 52 (Part C) of the 3-part phase 3 LIBERTY EoE TREET study.

Results

Part B BL characteristics were similar across groups. At Week 52 of Part C, 84.6% of patients in the DPL/DPL and 67.6% of patients in the PBO/DPL groups achieved peak eos count of ≤6 eos/hpf and mean (SD) absolute change from Part B BL in DSQ score was −30.26 (15.39) for DPL/DPL and −27.25 (11.46) for PBO/DPL patients. At Week 52, 100% of patients in the DPL/DPL and 78.4% PBO/DPL groups achieved peak eos count of <15 eos/hpf. Compared to Part B BL, peak eos count, EREFS, HSS grade and stage scores were reduced, and EDP and T2 normalized enrichment scores were suppressed in the DPL/DPL and PBO/DPL groups at Week 52 (Table). Dupilumab demonstrated an acceptable safety profile in Part C; the most common (occurring ≥10%) treatment-emergent adverse events in the DPL/DPL and PBO/DPL groups were injection-site reactions (13.5% and 10.8%), COVID-19 (9.5% and 10.8%), and nasopharyngitis (4.1% and 10.8%).

Conclusion

As observed in Part A/C, dupilumab qw demonstrated persistent improvements in clinical, symptomatic, histologic, endoscopic, and molecular features of EoE up to 52 weeks and Overall safety was consistent with the known dupilumab safety profile. PBO patients from Part B who received dupilumab in Part C showed similar efficacy to dupilumab qw patients of Part B.

Disclosure

Dellon ES: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Landos, LucidDx, Morphic, Nextstone Immunology, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio – consultant; Adare/Ellodi, Allakos, Arena, AstraZeneca, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda – research funding; Allakos, Holoclara, Invea – educational grant.
Rothenberg ME: Allakos, AstraZeneca, BMS, Celldex, ClostraBio, Ellodi Pharmaceuticals, GSK, Nextstone One, PulmOne, Regeneron Pharmaceuticals Inc., Revolo, Sanofi, Santa Ana Bio, Serpin Pharma, Spoon Guru ‒ consultant; Celldex, ClostraBio, Nextstone One, PulmOne, Santa Ana Bio, Serpin Pharma, Spoon Guru ‒ equity interest; Mapi Research Trust ‒ royalties from PEESSv2; Teva Pharmaceuticals ‒ royalties from reslizumab; UpToDate ‒ royalties; inventor of patents owned by Cincinnati Children’s Hospital.
Collins MH: Alimentiv, Allakos, Arena, AstraZeneca, BMS, Calypso, EsoCap, GSK, Regeneron Pharmaceuticals, Inc., Shire – consultant.
Hirano I: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eli Lilly, EsoCap, Gossamer Bio, GSK, Nexstone Immunology, Parexel/Calyx, Phathom, Receptos/BMS, Regeneron Pharmaceuticals Inc., Sanofi, Shire/Takeda – consultant; Adare/Ellodi, Allakos, Receptos/BMS, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding.
Chehade M: Adare/Ellodi, Allakos, AstraZeneca, BMS, Phathom; Recludix, Regeneron Pharmaceuticals Inc., Sanofi, Shire/Takeda – consultant; Adare/Ellodi, Allakos, AstraZeneca, Danone, Regeneron Pharmaceuticals Inc., Shire/Takeda – research funding.

Introduction

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The safety of tofacitinib was evaluated in the Overall Cohort, which consisted of 6 studies: 4 randomised, placebo-controlled Phase (P)2/3 studies (NCT00787202; NCT01465763; NCT01458951; NCT01458574), an open-label, long‑term extension study (NCT01470612) and a randomised P3b/4 study (NCT03281304). We report final safety analyses from the tofacitinib UC clinical programme of ≤9.2 years of tofacitinib exposure (cut off date: 18 April 2022).

Aims & Methods

This analysis included 1157 patients (pts) receiving tofacitinib 5 or 10 mg twice daily (BID; predominant dose [PD]) in the Overall Cohort and a previously reported 52-week Maintenance Cohort.^1,2 Proportions and incidence rates (IRs; unique pts with events/100 pt-years of exposure) were evaluated for deaths and adverse events of special interest (AESI): serious infections; herpes zoster (HZ); opportunistic infections (OIs); malignancies (excluding non‑melanoma skin cancer [NMSC]); NMSC; major adverse cardiovascular events (MACE); deep vein thrombosis (DVT); pulmonary embolism (PE); and gastrointestinal (GI) perforations.

Results

In the Overall Cohort, 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID; 938 (81.1%) received a PD of 10 mg BID; 552 (47.7%) pts had received tofacitinib for ≥2 years. Median treatment duration was 1.7 years (mean 2.8; range 0.0–9.2). IRs (95% CI) for all tofacitinib in the Overall Cohort (Table): deaths 0.24 (0.10, 0.48); serious infections 1.80 (1.37, 2.32); HZ (non-serious and serious) 3.24 (2.63, 3.94); serious HZ 0.24 (0.10, 0.48); OIs 0.96 (0.65, 1.36); malignancies (excluding NMSC) 0.88 (0.59, 1.26); NMSC 0.71 (0.45, 1.07); MACE 0.27 (0.12, 0.52); DVT 0.06 (0.01, 0.22); PE 0.18 (0.07, 0.40); and GI perforations 0.09 (0.02, 0.27).

Conclusion

IRs for AESI remained stable over an extended period of time (≤9.2 years) with the inclusion of the P3b/4 final data and were consistent with prior Overall Cohort analyses (≤7.8 years).^1,2 The safety profile of tofacitinib in the UC clinical programme was consistent with that observed in other indications.^3,4

References

1. Sandborn WJ et al. Clin Gastroenterol Hepatol 2019;17:1541–50.
2. Sandborn WJ et al. J Crohns Colitis 2023;17:338–51.
3. Cohen SB et al. RMD Open 2020;6:e001395.
4. Burmester GR et al. Drug Saf 2020;43:379–92.

Disclosure

Julian Panés has received grants and/or research support from AbbVie and Pfizer Inc, is a member of the speakers’ bureau for Abbott, Ferring, Janssen, Pfizer Inc and Takeda, has been an advisory board member for AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer Inc, Progenity, Prometheus, Protagonist, Revolo, Robarts, Sanofi, Takeda, Theravance and Wasserman, and has developed educational presentations for AbbVie, Janssen, Pfizer Inc, Roche and Takeda. Geert R. D’Haens has received speaker fees from AbbVie, Boehringer Ingelheim, Celltrion, Johnson & Johnson, Pfizer Inc, Takeda and Tillotts, and has been an advisory board member for AbbVie, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Cosmo, Eli Lilly, Galapagos, GlaxoSmithKline, Johnson & Johnson, Takeda, Pfizer Inc, Polpharma, Prometheus, Tillotts and Ventyx. Bruce E. Sands has acted as a consultant for, or received speaker fees from, AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, GlaxoSmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kallyope, Merck, MiroBio, Morphic, MRM Health, OSE Immunotherapeutics, Pfizer Inc, Progenity, Prometheus, Protagonist, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance, TLL Pharmaceutical, USWM Enterprises, Ventyx and Viela Bio, and is a shareholder of Ventyx. Siew C. Ng has received grants and/or research support from AbbVie, Ferring, Janssen and Olympus, has received speaker fees from AbbVie, Ferring, Janssen, Menarini, Pfizer Inc, Takeda and Tillotts, has been an advisory board member for AbbVie, Ferring, Janssen and Pfizer Inc, holds a Directorship with Microbiota I Center, and is the scientific co-founder and a shareholder of GenieBiome Limited. Nervin Lawendy is an employee and shareholder of Pfizer Inc. Nicole Kulisek is an employee and shareholder of Pfizer Inc. Xiang Guo is an employee and shareholder of Pfizer Inc. Joseph Wu is an employee and shareholder of Pfizer Inc. Ivana Vranic is an employee and shareholder of Pfizer Inc. Remo Panaccione has received grants and/or research support from AbbVie, Janssen, Pfizer Inc, and Takeda, and has acted as a consultant for and/or received speaker fees from Abbott, AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos, Eisai, Elan, Eli Lily, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion, Pendopharm, Pfizer Inc, Progenity, Prometheus, Protagonist, Roche, Sandoz, Satisfai Health, Shire, Sublimity, Takeda, Theravance, Trellus, Viatris and Ventyx. Séverine Vermeire has received grants from AbbVie, Galapagos, MSD, Pfizer Inc, and Takeda, has acted as a consultant for AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CVasThera, Dr Falk Pharma, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead Sciences, Hospira, IMIdomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MRM Health, MSD, Mundipharma, Pfizer Inc, ProDigest, Progenity, Prometheus, Robarts, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts and Zealand, and has received speaker fees from AbbVie, Dr Falk Pharma, Ferring, Hospira, MSD, Takeda and Tillotts.