Introduction

Etrasimod is an oral, once-daily, selective sphingosine 1-phosphate_1,4,5 receptor modulator. Within the phase 2/3 CULTIVATE trial (NCT04173273), we report extension data on the efficacy, safety and tolerability of etrasimod in patients with moderately to severely active Crohn’s disease (CD) from substudy A, a phase 2, randomised, double-blind study.

Aims & Methods

Adults (18–80 years) who completed the 14-week induction phase (data reported previously¹) were eligible for the 52-week extension period. Patients receiving etrasimod 3 mg during induction continued this treatment within the extension period, regardless of response. Etrasimod 2 mg responders at Week 14 continued treatment during the extension period, while nonresponders were re‑randomised (1:1) to etrasimod 2 or 3 mg. Two analyses were performed based on two approaches for patients entering extension: treat-through (TT; outcomes reported for all randomised patients regardless of Week 14 response) and responders only (RO; outcomes reported for Week 14 responders only). Both used non‑responder imputation. The primary endpoint was the achievement of endoscopic response (defined by endoscopic remission or ≥50% decrease in Simple Endoscopic Score in Crohn’s Disease) at Week 52; other endpoints included the achievement of clinical remission based on Crohn’s Disease Activity Index (CDAI; <150) and based on PRO2 (<8) at Week 52 (Table). Treatment-emergent adverse events (TEAEs) were reported for the safety set (all randomised patients who received ≥1 dose).

Results

In total, 65 patients (safety set) were enrolled in the extension period with 38 completing the study; patient demographics and baseline characteristics are shown in the Table. For the TT analysis, 14.3% and 19.5% of patients receiving 2 mg or 3 mg etrasimod, respectively, achieved endoscopic response, 28.6% and 34.1% achieved CDAI remission, and 19.0% and 36.6% achieved PRO2 remission at Week 52 (Table). Among Week 14 responders (RO), 23.1% and 33.3% of patients receiving 2 mg or 3 mg etrasimod, respectively, achieved endoscopic response, 46.2% and 54.2% achieved CDAI remission, and 30.8% and 58.3% achieved PRO2 remission at Week 52 (Table). Most TEAEs were mild or moderate. Nine TEAEs led to discontinuation; one was deemed treatment-related (Table). No deaths or TEAEs of macular oedema or malignancies were reported.

Conclusion

Both etrasimod doses remained well tolerated with no new safety signals. This non-placebo-controlled study suggests that etrasimod may be effective in moderately to severely active CD, with higher efficacy at the 3 mg dose. Placebo-controlled studies are ongoing.

References

1. D’Haens G et al. J Crohns Colitis 2023; 17: i764–i765.

Disclosure

GD, Advisor: AbbVie, Alimentiv, AstraZeneca, BI, BMS, Celltrion, Cosmo, Lilly, Galapagos, GSK, J&J, Pfizer, Polpharma, Prometheus, Takeda, Tillotts, and Ventyx. Speaker fees: AbbVie, BI, Celltrion, Lilly, J&J, Pfizer, Takeda, and Tillotts; MCD, Consulting fees: AbbVie, Abivax, Arena, AstraZeneca, BMS, Lilly, Galapagos, Genentech, Gilead, Janssen, Merck, Pfizer, Prometheus, Prometheus Laboratories, Sphyre, Takeda, and UCB. Shareholder/Royalties: Trellus Health. Directorship/Ownership interest: Trellus Health. LPB, Consulting fees: AbbVie, Abivax, Alimentiv, Alma Bio, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, HAC, IAG Image Analysis, Index, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fisher, Tigenix, Tillotts, Viatris, Vifor, Vectivbio, Ventyx, and Ysopia. Grants: Celltrion, Fresenius Kabi, and Takeda. Lecture/speaker bureau: AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genetech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Tillotts, Viatris, and Vifor; SD, Lecture/speaker fees: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda. Consulting/advisory fees: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, BI, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, J&J, MSD, Mundi, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor. Directorship/Ownership: Gastroenterology and Endoscopy. BES, Consulting fees: AbbVie, Abivax, Adiso, Agomab, Alimentiv, Amgen, AnaptysBio, Arena, Artugen, AstraZeneca, Biora, BI, Boston, BMS, Calibr, Celgene, Celltrion, ClostraBio, Enthera, Equillium, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech/Roche, Gilead, GSK, Gossamer Bio, Index, Innovation, Janssen, Kaleido, Kallyope, Lilly, Merck, Mobius Care, Morphic, MRM Health, Nexus, Nimbus Discovery, Odyssey, Palisade Bio, Pfizer, Progenity, Prometheus, Prometheus Laboratories, Protagonist, Q32 Bio, Rasayana, Sun, Surrozen, Takeda, Target RWE, Teva, Theravance, TLL, TR1X, Union, and Ventyx. Speaking fees: AbbVie, Abivax, BMS, Janssen, Lilly, Pfizer, and Takeda. Research grants: BMS, Janssen, Pfizer, and Takeda. Stock and Stock options: Ventyx. Other support: Abivax, BMS, Lilly, Janssen, Pfizer, and Takeda. AY, Consulting fees: AbbVie, Arena, BMS, Pfizer, and Takeda. Lecture fees: AbbVie and BMS. MVC, Grant support: BMS, Janssen, Pfizer, and Novartis. Consulting fees: AbbVie, Arena, BMS, Celltrion, Fresenius Kabi, Janssen, Lilly, Medtronic, Pfizer, Prometheus, and Takeda. Speaker fees: AbbVie, BMS, Janssen, Lilly, Medtronic, Pfizer, and Takeda. IM, DB, AM, MK, LVC, GG, HT, CS, Shareholder and employee: Pfizer; LVC Shareholder and employee: BMS; SS, Lecture/speaker fees: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Falk, Fresenius, Janssen, MSD, Pfizer, and Takeda. Consulting/advisory fees: AbbVie, Arena, Biogen, BMS, Celgene, Celltrion, Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Takeda, Theravance, and Ventyx. BF, Senior Scientific Director: Alimentiv. Speaker fees: AbbVie, Janssen, and Takeda. Consulting/advisory board: AbbVie, AbolerIS, AgomAB, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Atomwise, Avoro Capital Advisors, BioJamp, Biora, BI, Boxer, Celgene/BMS, Celsius, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge Bio, Hot Spot, Index, Imhotex, Immunic, JAKAcademy, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Play to Know AG, Progenity, Prometheus and Diagnostics, Protagonist, PTM, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx, VHSquared Ltd, Viatris, Ysios, Ysopia, and Zealand. Shareholder: Gossamer; SV, Lecture/speaker fees: AbbVie, Dr. Falk, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda, and Tillotts. Consulting/advisory fees: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, BI, Celgene, CVasThera, Dr Falk, Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, J&J, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundi, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts AG, and Zealand. Grant/research support: AbbVie, Galapagos, Janssen, MSD, Pfizer, and Takeda.

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.