Introduction

Between 50% and 70% of patients with Crohn’s disease (CD) will require an ileocecal resection. Surgery is not curative, and endoscopic recurrence is frequently observed at the anastomosis site and/or in the neo-terminal ileum.
The objective of this study was to analyse the mucosa-associated ileal microbiota at the time of surgery and during the colonoscopy performed 6 months later and to identify predictive factors of post-operative endoscopic recurrence.

Aims & Methods

Patients were recruited from 15 centres within the REMIND group. Since September 2010, the REMIND group has established a homogeneous, prospective, multicenter cohort (POP-REMIND, NCT03458195) of patients undergoing surgery for ileal and/or ileocolonic Crohn’s disease. Samples were collected from the surgical specimen and during endoscopy, centrally stored in a biobank, and analysed to identify factors associated with recurrence.
Inclusion criteria were: age ≥18 years, ileal or ileocecal CD requiring intestinal resection. Data were collected using an electronic case report form (eCRF). Post-operative treatment was prescribed according to a predefined algorithm. Clinical, therapeutic, biological, and endoscopic data (Rutgeerts classification) were collected 6 months after surgery.
The composition of the mucosa-associated ileal microbiota was analysed at the time of surgery in 140 patients (M0) and in 125 samples at the colonoscopy performed 6 months later (M6), using ultra-deep 16S and ITS2 sequencing (MiSeq, Illumina) to characterize bacterial and fungal microbiota.
We specifically selected patients who had not received antibiotics during the perioperative period to avoid biasing the analysed signal. Sequencing data were processed using the DADA2 pipeline. Alpha and beta diversity and microbiota composition were analysed. Bacterial taxa associated with clinical parameters were identified using MaAsLin2 (Multivariate Association with Linear Models), accounting for CD phenotype and treatments.

Results

We observed numerous differences in the ileal bacterial and fungal microbiota between M0 and M6, and between patients who experienced recurrence (>i2a) and those who were in remission at M6. At M6, the Rutgeerts score was the main factor associated with variability in microbiota composition. The abundance of certain species, notably a decrease of Faecalibacterium prausnitzii, or increase of Fusobacterium nucleatum and Akkermansia muciniphila, was differentially associated with a whole range of levels of the Rutgeerts score or with more specific scores characterizing the inflammation of the anastomosis or the ileum. In addition, machine learning approaches displayed better performances when considering the Rutgeerts score as a multilevel prediction instead of a binary classification, further confirming the need to consider its full range. Finally, we investigated the microbial community dynamics, which highlighted a denser network organisation after surgery and in the absence of recurrence, along with changes in keystone species.

Conclusion

The ileal microbiota associated with post-operative recurrence in CD follows a dynamic process characterized by several waves of alterations. The link between ileal microbiota and disease recurrence varies depending on whether the lesions are located at the anastomosis or ileum sites, supporting a different underlying pathogenesis for the inflammatory process at these two locations.

Introduction

Tumour necrosis factor-like ligand 1A (TL1A) is a novel therapeutic target for inflammatory bowel disease. Patients (pts) with moderately to severely active ulcerative colitis (UC) treated with the anti-TL1A antibody, RO7790121 (formerly PF-06480605 and RVT-3101), showed significant endoscopic improvement and adequate safety in the phase 2a TUSCANY trial.¹ Here, we report data from the global, randomised, double-blind, placebo-controlled, dose-ranging phase 2b TUSCANY-2 (NCT04090411) trial evaluating the efficacy and safety of subcutaneous (SQ) doses of RO7790121 in adult pts with moderately to severely active UC (total Mayo Score [tMS] ≥6, endoscopic subscore ≥2) who had previously failed conventional/advanced therapy.

Aims & Methods

Pts were randomised to receive RO7790121 SQ 50mg, 150mg, 450mg or placebo (PBO) monthly during the 12-week induction period and RO7790121 SQ 50mg, 150mg or 450mg monthly during the treat-through 40-week maintenance period. Efficacy endpoints were assessed at weeks 14 and 56 in the induction and maintenance intent-to-treat analysis sets, respectively. The primary efficacy endpoint was clinical remission at week 14 by tMS. Safety was assessed throughout the induction and maintenance periods. The secondary endpoint of clinical remission using modified Mayo Score (mMS) is aligned to updated FDA guidance. Other secondary endpoints included clinical remission (by tMS and mMS) at week 56 and endoscopic improvement at weeks 14 and 56. Efficacy analysis by pre-defined biomarker subgroups was also performed.

Results

Overall, 245 pts were randomised and treated; 228 completed the induction and 224 entered the maintenance period of the study. At week 14, 25.5%, 23.3% and 23.9% of pts in the RO7790121 50mg, 150mg, 450mg arms, respectively vs 11.6% in PBO experienced clinical remission by tMS (p>0.05 [Table]). The proportion of pts achieving clinical remission using mMS at week 14 was 29.8%, 35.0% and 31.8% in the RO7790121 50mg, 150mg, 450mg arms, respectively vs 11.6% in PBO (nominal p<0.05). Improvements in clinical remission were sustained throughout the maintenance period (Table). A greater proportion of pts demonstrated endoscopic improvement across all doses of RO7790121 vs PBO at week 14 and week 56. Numerically greater treatment effects were observed in biomarker-positive pts relative to all-comer pts. During the induction period, 47.8% (117/245) of pts reported ≥1 treatment-emergent adverse event (TEAE). The most common TEAEs (occurring in ≥5% pts overall) were anaemia (5.3%) and headache (5.3%). In the induction period, 10 pts experienced serious TEAEs (PBO=4; 50mg=3; 450mg=3); 2 treatment-related (PBO=1; 450mg=1). No pts discontinued the study due to TEAEs. A generally similar safety profile was observed during the maintenance period.

Conclusion

Data from the phase 2b TUSCANY-2 dose-ranging study suggests that RO7790121 has a favourable benefit/risk profile with clinically meaningful improvements in pts with moderately to severely active UC. A phase 3 study will be conducted to confirm these results.

Table. Summary of efficacy outcomes at week 14 and week 56

References

1. Danese S, et al. Clin Gastroenterol Hepatol 2021;19:2324–32.e6.

Disclosure

This study was sponsored by Pfizer Inc and Roivant Sciences Ltd. Medical writing support, under the direction of the authors, was provided by Margarita Gkrava, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.
SD, consultancy/advisory role/board: AbbVie, Alimentiv, Allergan, Amgen, AMT, AstraZeneca, Athos Therapeutics, Biogen, Boehringer, BMS, Celgene, Celltrion, Dr Falk Pharma, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, J&J, Lilly, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc, TiGenix, UCB, Vial, Vifor. Lecture fees: Abbvie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda.
JRA, consulting/advisory role/board: Abbvie, Adiso, BMS, Ferring, Finch Therapeutics, GSK, Janssen, Merck, Pfizer, Roivant, Seres Therapeutics. Speakers’ bureau: Abbvie, BMS, Janssen. Research funding: Janssen, Merck, Pfizer.
SS, consulting/advisory role/board: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, BMS, Celgene, Celltrion, Dr Falk Pharma, Ferring, Fresenius Kabi, Galapagos/Gilead Sciences, Hikma Pharmaceuticals, I-Mab, Janssen, Lilly, Morphic Therapeutic, MSD, Mylan, Pfizer, Protagonist Therapeutics, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma, and Ventyx Biosciences.
LP-B, consulting/advisory role/board : Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, AMT, Arena, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, Hac Pharma, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, 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. Speakers’ Bureau: Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Tillots, Viatris, Vifor. Research funding: Celltrion, Fresenius Kabi, Takeda. Support travel: Abbvie, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, Tillots.
VJ, employment: Western University, London Health Sciences Centre, Alimentiv. Consulting or advisory role/board : AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei, Asieris, AstraZeneca, Avoro Capital, BMS, Celltrion, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion. Speakers’ bureau: AbbVie, Ferring, BMS, Galapagos, Janssen, Pfizer, Shire, Takeda, Fresenius Kabi.
GRD, consulting/advisory role/board: Alimentiv, Abbvie, BMS, Boehringer, Celltrion, GSK, Immunic, Index, J&J, Lilly, Polpharm, Takeda, Tillotts, Ventyx, Pfizer. Speakers’ bureau: Lilly, Pfizer, Takeda. Research funding: Cellitron, Lilly, Pfizer, Takeda.
JK, no COI.
RWL, consulting/advisory role/board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus, Takeda. Research funding: Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, Joanna Tiddy grant, McKusker Charitable Foundation.
AJY, consulting/advisory role/board: Abbvie, Takeda, Celltrion, BMS, J&J, Abivax.
JMM, employment/stock/other ownership interests: Roche/Genentech.
DB, employment: F. Hoffmann-La Roche.
KL, employment: Roche/Genentech.
CS, employment/stock/other ownership interests: Roche/Genentech.
KEH, employment/stock/other ownership: Pfizer.
BGF, stock/other ownership interests: Connect Biopharm, EnGene. Honoraria/consulting/advisory role/board: AbbVie, Abivax, Adiso, Agomab, Allianthera, Amgen, AnaptysBio, Arena Pharma, Avoro Capital, Atomwise, BioJamp, Biora Therapeutics, Blackbird Laboratories, Boehringer, Boxer Capital, Celsius Therapeutics, Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Equillium, Ermium, First Wave, Forbion, Galapagos, Galen Atlantica, Roche/Genentech, Gilead, Gossamer, GSK, Hinge Bio, Index Pharma, Imhotex, Immunic Therapeutics, Intercept, JAKAcademy, Janssen, Japan Tobacco, Kaleido, Klick Health, Landos Biopharma, Lenczner Slaght, LifeSci Capital, Lilly, Lument, Mage Biologics, Mestag, Millennium, MiroBio, Monte Rosa, Morgan Lewis, Morphic Therapeutics, Mylan, Nexys Therapeutics, Nimbus Therapeutics, OM Pharma, OrbiMed, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Roivant/Televant, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Sobi, Spyre Therapeutics, Surrozen, Synedgen, Takeda, Teva, Thelium, Tigenix, Tillotts, Triastek, Ventyx Biosciences, Zagbio, Zealand Pharma. Speakers’ Bureau: Takeda, Janssen, Abbvie.