Introduction

Tracheoesophageal fistula (TEF) is a congenital or acquired pathology characterized by communication between the posterior tracheal and the anterior esophageal wall. Congenital TEF type E, “H” fistula without esophageal atresia, accounts for only 4% of cases. So far, minimal-invasive surgical techniques are accepted as first line therapy. Endoscopic interventions have been described to be safe and effective in the management of TEF, with lower morbidity and mortality compared to surgical interventions.

Aims & Methods

We present a case of a successful endoscopic closure of a TEF using a new endoscopic, through-the-scope suture device (TTS-SD, X-Tack, Boston Scientific).

Results

A 37-month-old boy presented at our clinic in early 2023 with recurrent postprandial coughing, choking and bronchopulmonary infections. At index endoscopy only a small pore was detected without evidence of a relevant TEF. Patient was rescheduled after 6 months. Over this period, symptoms significantly worsened with non-percentile-appropriate growth/weight gain. At follow-up (FU) endoscopy a significant H-fistula was noted at 13 cm from the dental arch. After freshening the fistula pore with argon plasma coagulation (APC), a fully covered, self-expanding metal stent (fcSEMS) of 10x80 mm was inserted. This stent dislodged into the stomach after a few days and was replaced by a larger fcSEMS (20 mm diameter), which was only tolerated for another few days. Immediately after removal, the TEF was closed endoscopically using three TTS clips. The boy was symptom-free for 3 weeks post-intervention, but then experienced a sudden recurrence of the known symptoms. Endoscopically, the clips were completely dislodged, the TEF was detectable again. Another attempt with TTS clips yielded identical results. In March 2024, an endoscopic closure was performed using the novel TTS-SD, which can be applied through the working channel of a regular gastroscope. After freshening the scarred fistula with APC and brushes, four helices were screwed into the submucosa, the defect was continuously sutured in a cross-cross pattern. Immediately after the intervention the patient was free of symptoms. Endoscopic FU after 2 and 6 weeks showed persistent closure of the TEF with complete resolution of symptoms.

Conclusion

Congenital TEFs can be effectively managed using endoscopic techniques. In young children, fcSEMS appear to be less efficacious when compared to direct closure of the fistula. The introduction of the novel TTS-SD, has enabled successful treatment of the TEF in the presented case. The utilization of the TTS-SD represents a significant advancement in our therapeutic armamentarium for managing these complex cases especially in a small working space. However, there is need for long-term follow-up data.

Disclosure

Prof. Dr. Mark Ellrichmann received lecture honorarium, consultation fees and study support from Boston Scientific.
All other auhtors have nothing to declare.

Introduction

Risankizumab (RZB), a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), demonstrated substantial improvements in clinical and endoscopic outcomes in patients (pts) with active Crohn’s disease (CD) in the phase 3 studies (ADVANCE [NCT03104413], MOTIVATE [NCT03105128], and FORTIFY [NCT03105102]).^1-2 In the FORTIFY study, clinical remission rates at week 52 were higher than expected in responders to induction RZB who were randomized to placebo (WD PBO) for maintenance, suggesting a durable effect of RZB. In this study, we investigated the molecular mechanisms associated with sustained clinical effects of RZB in CD pts in the phase 3 studies.

Aims & Methods

Bulk RNA sequencing was performed on colon biopsies collected longitudinally from a subset of pts in the phase 3 studies (True PBO, n=23; WD PBO, n=29; pooled RZB 180 and 360 mg, n=77) with matched samples at baseline (BL), wk12 (induction), and wk52 (maintenance). Differentially expressed genes (DEGs) from BL to wk52 were identified with linear mixed-effect models (false discovery rate ≤0.05) in all pts as well as in pts who achieved clinical remission (average daily stool frequency ≤2.8 and not worse than BL and average daily abdominal pain score ≤1 and not worse than BL) at wk52 and those who achieved maintenance of clinical remission from wk12 to wk52. Pathway enrichment analyses were performed with Ingenuity Pathway Analysis (IPA). Cell type enrichment analyses based on gut cell signatures from Buckley et al³ was conducted using Gene Set Variation Analysis (GSVA).

Results

Analysis of DEGs in colon biopsies from all pts yielded a highly significant subset of genes modulated from BL to wk52 in the WD PBO and RZB treatment arms. Shared upregulated DEGs across the WD PBO and RZB groups (MT-ND6, MT-ND4, MT-ND5, MT-ATP6, MT-ND4L, MT-ND1, MT-ND2, MT-CYB, MT-ND3, MT-CO2, MT-CO3, MT-CO2 and EIF3C) are associated with reduced mitochondrial dysfunction and upregulation of mitochondrial oxidative phosphorylation. Modulation of these genes were also enriched in pts who achieved wk52 clinical remission as well as pts who achieved maintenance of clinical remission from wk12 to wk52. Next, we validated the enrichment of the MT genes (based on the top 13 upregulated genes) at the patient level and found that all 13 shared MT gene signatures were significantly enriched at wk52 compared to BL and wk12 in both the WD PBO and RZB treatment arms. Additionally, the MT signature scores were comparable between the WD PBO and RZB arms at wk52. Cell type enrichment analyses further revealed that all 13 MT genes were expressed at higher levels in epithelial cells compared to other immune cell subsets, highlighting their potential role in epithelial cell function. These MT genes were also enriched in colonocytes, enterocytes, and LRG+ stem cells of pts who achieved wk52 clinical remission in both WD PBO and RZB groups, with significantly higher expression at wk52 compared to BL and wk12.

Conclusion

In this study, we identified molecular mechanisms indicating an immunometabolic shift, characterized by downregulation of canonical inflammatory pathways (such as neutrophil degranulation) and an enrichment of oxidative phosphorylation and enhanced mitochondrial activity in RZB-treated pts who demonstrated sustained clinical remission through 52 weeks of drug withdrawal. Durable clinical effects observed with RZB could be due to the enrichment of MT genes in colonic epithelial cells in the gut, which may signify RZB’s ability to restore mitochondrial function and energy metabolism.

References

1. Schreiber SW, et al. J Crohn's Colitis. 2021;15(S1).
2. Ferrante M, et al. The Lancet. 2022;399(10340):2031-2046.
3. Thomas T, et al. Nat Immunol. 2024;25:2152–2165.

Disclosure

Author Disclosures
Nick Powell has received research grants from AstraZeneca, Bristol Myers Squibb, CCUK, Celltrion Healthcare, Helmsley Charitable Trust, Pfizer, and Takeda; received personal fees from AbbVie, Allergan, AstraZeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Galapagos, GlaxoSmithKline, Janssen, Pfizer, Takeda, and Roche; served as a speaker or on the advisory board for AbbVie, Allergan, AstraZeneca, Bristol Myers Squibb, Celgene, Dr Falk, Galapagos, and Vifor; and serves on the data safety monitoring board for AstraZeneca and Bristol Myers Squibb.
Bram Verstockt has received research support from AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares and Takeda; speaker’s fees from AbbVie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris; consultancy fees from AbbVie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Mylan, Inotrem, Ipsos, Janssen, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma, and Viatris; and stock options from Vagustim.
Geert D’Haens has received consulting and/or lecture fees from AbbVie, ActoGeniX, AIM, Boehringer Ingelheim, Centocor, ChemoCentryx, Cosmo Technologies, Dr Falk Pharma, Elan Pharmaceuticals, enGene, Ferring, Galapagos, Giuliani SpA, Given Imaging, GlaxoSmithKline, Janssen, MSD, Neovacs, Novo Nordisk, Otsuka, PDL BioPharma, Pfizer, Receptos, Salix, SetPoint, Shire, Schering-Plough, Takeda, Tillotts, UCB Pharma, Versant and Vifor Pharma; research grants from AbbVie, Dr Falk Pharma, Given Imaging, Janssen, MSD and PhotoPill; and speaking honoraria from AbbVie, Ferring, MSD, Norgine, Shire, Tillotts, Tramedico and UCB Pharma.
Naim Al Mahi, Stephen Laroux, Ari Stromberg, Heath Guay, and Buvana Ravishankar are full-time employees of AbbVie and may own AbbVie stock or stock options.
James Lindsay has served as a consultant and an advisory board participant for AbbVie, Atlantic Healthcare, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead, GSK, Janssen, MSD, Napp, Pfizer, Shire, Takeda, and Vifor Pharma; has received speaker fees and sponsorship for academic meetings from AbbVie, Ferring Pharmaceuticals, Janssen, MSD, Napp, Norgine, Pfizer, Shire, Tillotts Pharma, and Takeda; and has received investigator-led research grants from AbbVie, Gilead, Pfizer, Shire and Takeda.


Funding
AbbVie funded this trial and participated in the trial design, research, analysis, data collection, interpretation of data, and the review and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. AbbVie and the authors thank the patients, study sites, and investigators who participated in this clinical trial.

Introduction

Obefazimod is an investigational, oral, once-daily, small molecule which enhances expression of microRNA-124 and is currently in phase 3 clinical trials for the treatment of patients with moderately to severely active ulcerative colitis (UC) [1]. Obefazimod demonstrated efficacy and safety in patients with UC at week-8 in a placebo-controlled, Phase 2b induction trial and in the subsequent open-label maintenance (OLM) study [2]. Here we present efficacy and safety among patients who did and those that did not achieve clinical response at week 8 of the double-blind induction trial.

Aims & Methods

Patients received placebo or obefazimod 25mg, 50mg or 100mg once daily (od) during the Phase 2b, induction trial and, irrespective of their clinical response, could enter the optional 96-week OLM study with obefazimod 50mg od. Patients were followed monthly for safety and efficacy. This analysis evaluates efficacy (at week 48) and safety (through week 96) among patients who achieved and those who did not achieve clinical response (decrease from baseline in the Modified Mayo score (MMS) ≥ 2 points and ≥30% from baseline, plus a decrease in rectal bleeding sub-score (RBS) ≥ 1 or an absolute RBS ≤ 1) at week 8 of double-blind induction and continued treatment in the OLM.

Results

Among the 217 patients who participated in the OLM, 57% (124/217) achieved clinical response at week 8 of the induction trial (CR group), and 43% (93/217) did not (NCR group). Proportions of patients achieving efficacy endpoints were numerically higher within the CR group than those observed in NCR group. At week 48, 66% of CR patients and 40% of NCR patients achieved clinical remission; 86% of CR patients and 75% of NCR patients achieved clinical response; endoscopic improvement was achieved by 70% of CR patients and by 50% of NCR patients, and endoscopic remission was achieved by 38% of CR patients and 27% of NCR patients (Table 1). There was no significant difference in the safety profile between these two subpopulations.

Table 1: Efficacy at week 48 of open-label maintenance study among clinical responders and non responders at week 8 of induction trial

Efficacy Endpoint, % (n)	Patients with clinical response at week 8 (N=124)	Patients with no clinical response at week 8 (N=93)
Clinical remission	66.1 (82)	39.8 (37)
Clinical response	86.3 (107)	75.3 (70)
Endoscopic improvement	70.2 (87)	49.5 (46)
Endoscopic remission	37.9 (47)	26.9 (25)

Non-responder imputation (NRI) was used for missing efficacy data; clinical remission: stool frequency sub-score ≤1, RBS = 0 and endoscopic sub-score ≤1; clinical response: decrease from baseline in the Modified Mayo score (MMS) ≥ 2 points and ≥30% from baseline, plus a decrease in rectal bleeding sub-score (RBS) ≥ 1 or an absolute RBS ≤ 1; endoscopic improvement: endoscopic sub-score ≤1; endoscopic remission: endoscopic sub-score = 0

Conclusion

Substantial proportions of patients treated with obefazimod 50 mg od achieved clinical outcomes at week 48 of an open label maintenance study, irrespective of whether they achieved clinical response at week 8 of the prior induction trial. Patients achieving clinical response at week 8 of the induction trial consistently showed higher efficacy rates throughout the 48-week open-label maintenance trial. The safety profile remains consistent over time, regardless of treatment response at week 8.

References

1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697
2. Vermeire S, et al. The Lancet Gastroenterology & Hepatology. 2022; 7: 1024-1035.

Disclosure

Bruce E Sands has served as a consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, 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 and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio, and stock options from Ventyx Biosciences.
Séverine Vermeire has received grants from AbbVie, J&J, Pfizer, Takeda and Galapagos; SV has received consulting and/or speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma.
Laurent Peyrin-Biroulet has received grants from Celltrion, Fresenius Kabi, Takeda; LPB has served as a consultant or received speaker’s fees from Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, Connect Biopharm , Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilea, Gossamer Bio, GSK, Hac Pharm, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopa, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vifor, Vectivbio, Ventyx, Ysopia.
Silvio Danese has served as consultant or received speaker’s fees from AbbVie, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer Inc, Tigenix, UCB Pharma, Vifor, Biogen, Celgene, Allergan, Celltrion, Sandoz, Boehringer Ingelheim.
Parambir Dulai received speaker’s fees from Abbvie, Abivax, Adiso, Bristol Meyer Squibb, Geneoscopy, GSK, Janssen, Lilly, Pfizer, Takeda.
Herbert Tilg has served as a consultant or received speaker’s fees from Abbvie, Abivax, Dr Falk Pharma, ferring, Galapagos, Microbiotica, MSD, Pfizer, Takeda.
Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).