Introduction

Sphingosine 1-phosphate (S1P) receptor modulators have been associated with an increased risk of macular oedema.¹ Etrasimod is an oral, once-daily, selective S1P_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC) and in development for the treatment of other immune-mediated inflammatory diseases.

Aims & Methods

We assessed the proportions and incidence rates (IRs; patients with events per 100 patient-years [PY] of exposure) of Macular oedema and Cystoid macular oedema in a comprehensive analysis of safety data from the etrasimod clinical programme. UC data were analysed in two cohorts: Placebo-controlled UC (completed phase [ph] 2 OASIS, ph 3 ELEVATE UC 52 and ELEVATE UC 12) and All UC (patients treated with etrasimod in the Placebo-controlled UC plus open‑label extension [OLE] studies; completed ph 2 OASIS OLE and ongoing ph 3 ELEVATE UC and ES101002 OLE studies, both datacut at 31 Jan 2022). Data from completed ph 2 studies in Crohn’s disease (CULTIVATE substudy A), and Placebo‑controlled studies in eosinophilic oesophagitis (VOYAGE), alopecia areata and atopic dermatitis (ADVISE) were also analysed.

Results

Across the etrasimod UC clinical programme, 942 patients received ≥1 dose of etrasimod 2 mg once daily (QD), with 757.9 PY of exposure. In the Placebo-controlled UC cohort, Macular oedema was reported in two patients (0.3%; IR 0.70) receiving etrasimod 2 mg QD (one patient with long-term corticosteroid use in ELEVATE UC 52 and one patient with prior uveitis in ELEVATE UC 12, which was not considered clinically significant by the investigator) and one patient (0.3%; IR 0.84) receiving placebo (ELEVATE UC 12). In the All UC cohort, one patient (0.1%; IR 0.13) receiving etrasimod 2 mg QD during the ELEVATE UC OLE reported two events of Cystoid macular oedema (Table). Four of five Macular oedema events began at Days 74–94, all were non-serious and only one event led to treatment discontinuation. No events of Macular oedema were reported in studies of etrasimod in other indications (Table).

Conclusion

The incidence of Macular oedema in patients treated with etrasimod in the clinical programme was low and generally comparable with placebo. These results are consistent with other S1P receptor modulators¹ and provide clinically relevant information on events of Macular oedema.

References

1. Bencardino S et al. J Clin Med 2023; 12: 5014.

Disclosure

MCD is a consultant for AbbVie, Abivax, AstraZeneca, Bristol Myers Squibb, Janssen, Lilly, Merck, Pfizer Inc, Prometheus Labs, Spyre and Takeda. JW, DB and IM are employees and shareholders of Pfizer Inc. AM is an employee of Pfizer Ltd and shareholder of Pfizer Inc. KL is an employee of Pfizer AG and a shareholder of Pfizer Inc. MG is an employee and shareholder of Pfizer AG. AA is a consultant for AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, Lilly, Lionhealth, MSD, Mylan, Nestlé, Pfizer Inc, Roche, Samsung Bioepis, Sandoz, Takeda and Tillots Pharma; has received grant/research support from Biogen, MSD, Takeda and Pfizer Inc; and lecture/speaker fees from AbbVie, Amgen, Biogen, Bristol Myers Squibb, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen, Lilly, Lionhealth, MSD, Novartis, Pfizer Inc, Roche, Samsung Bioepis, Sandoz, Takeda and TiGenix.

Introduction

Glepaglutide is a long-acting glucagon-like peptide 2 (GLP-2) analogue (Larsen B et al 2024) under development for the treatment of short bowel syndrome (SBS). Glepaglutide enhances intestinal absorption (Jeppesen P et al 2025), which may hypothetically lead to changes in the intestinal microbiota, mainly by slowing gastrointestinal transit time. This study evaluated whether the intestinal pro-absorptive effects of glepaglutide were related to changes in microbiota.

Aims & Methods

In this single-center, open-label, EASE SBS-4 phase 3b study, 10 patients with SBS (8 of the 10 with intestinal failure and 8 of the 10 without colon-in-continuity) were treated with glepaglutide 10 mg subcutaneous once weekly for 24 weeks. While the primary study finding demonstrated increased intestinal absorption assessed by metabolic balance studies, this study investigated whether treatment with glepaglutide was associated with changes in bacterial load and composition. Samples were obtained from either stool or ostomy effluent at baseline and after 24 weeks of treatment with glepaglutide. Bacterial load was quantified using a spike-in approach and composition was assessed by V3V4 16S rRNA gene sequencing.

Results

24 weeks of glepaglutide treatment did not significantly alter bacterial load nor composition of the intestinal microbiota of the patients. Bacterial load showed distinct differences between patients with and without a colon-in-continuity. In patients without a colon, most samples had values below 10⁹ cells per gram, whereas those with a colon-in-continuity had bacterial loads within the physiological range observed in healthy individuals, ranging from 10¹⁰ to 10¹¹ cells per gram feces (Vandeputte D et al 2017).
Microbiota composition also differed markedly by intestinal anatomy: patients without a colon-in-continuity had higher abundances of genera mainly associated with the upper gastrointestinal tract, such as Streptococcus, while those with a colon-in-continuity exhibited greater abundance of genera more commonly found in the lower gastrointestinal tract, including Bifidobacterium.

Conclusion

Treatment with the GLP-2 analogue glepaglutide increased intestinal wet weight and energy absorption without altering the intestinal bacterial microbiota in the patients with SBS participating in this study.
Bacterial load and composition were strongly influenced by intestinal anatomy.
In summary, this study indicated that changes in glepaglutide-induced intestinal absorption were not driven by the microbiota.

References

1. Larsen BD, Villadsen JS, Skarbaliene J, Melander C, Russell W, Petersen YM, Møller EH. Creating Glepaglutide, the first long-acting GLP-2 analogue to enable a ready-to-use injection. J Med Chem. 2025. 68 (3), 3134-3145.
2. Jeppesen PB, Vanuytsel T, Subramanian S, Joly F, Wanten G, Lamprecht G, Kunecki M, Rahman F, Nielsen TSS, Berner-Hansen M, Paper UF, Mercer DF. Glepaglutide, a long-acting glucagon-like peptide-2 analogue, reduces parenteral support in patients with short bowel syndrome: A phase 3 randomized controlled trial. Gastroenterology, 2025. 168(4):701-713.e6.
3. Vandeputte D et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature. 2017. 551(7681):507-511.

Disclosure

This study was funded by Zealand Pharma A/S

Introduction

Difficult-to-treat Crohn’s disease (CD), as defined by the International Organization for the Study of IBD (IOIBD), encompasses patients with persistent disease activity despite advanced therapies, complex phenotypes (e.g., penetrating complications), or post-surgical recurrence. Upadacitinib, a selective JAK1 inhibitor, has demonstrated efficacy in Western populations, yet data in Asian cohorts remain sparse. This study evaluates the effectiveness and safety of standardized induction regimen of upadacitinib (45mg qd) in Asian patients meeting IOIBD criteria for difficult-to-treat CD.

Aims & Methods

To assess the efficacy and safety of upadacitinib in Asian patients with difficult-to-treat CD, providing evidence for clinical decision-making, a retrospective, multicenter study was conducted from 8 Chinese tertiary centers (January 2023–January 2025) on difficult-to-treat Crohn’s disease patients who met IOIBD criteria. All patients received upadacitinib 45mg qd for 12 weeks. Clinical outcomes were assessed using the Crohn's Disease Activity Index (CDAI), with the primary outcome being clinical remission (CDAI <150) and the secondary outcome being clinical response (CDAI reduction ≥70) at week 12. Adverse events (AEs) were systematically recorded.

Results

We finally collected 151 patients who met IOIBD criteria(Table1). Among them, 147 patients presented failure of ≥2 biologics with distinct mechanisms, 3 patients had complex perianal disease and 1 patient had postoperative recurrence. The mean disease duration of these patients was 7.6 years (SD 4.5 years). At week 12, 71 patients (47.0%) achieved clinical remission, 66 patients (43.7%) showed clinical response, and 14 patients (9.3%) were non-responders. Adverse events occurred in 40 patients (26.5%): acne (n=13), anemia (n=13), leukopenia (n=3), fever (n=4), urinary tract infection (n=2), herpes zoster (n=2), folliculitis (n=1), amenorrhea (n=1), elevated creatine phosphokinase (n=1), and mediastinal tuberculosis (n=1). Most AEs were mild and resolved with oral medications.

Table1. Baseline Characteristics of Patients with Difficult-to-Treat CD Treated with UPA

Conclusion

This is the largest Asian cohort study of upadacitinib for difficult-to-treat CD. The drug demonstrated robust efficacy and a favorable safety profile. Notably, tuberculosis reactivation was rare. Standard dosing showed comparable effectiveness and tolerability to European data, underscoring upadacitinib as a strong therapeutic option in Asian populations.

References

1. Parigi TL, D'Amico F, Abreu MT, et al. Difficult-to-treat inflammatory bowel disease: results from an international consensus meeting. Lancet Gastroenterol Hepatol. 2023;8(9):853-859. doi:10.1016/S2468-1253(23)00154-1
2. Parigi TL, Massimino L, Carini A, et al. Prevalence, Characteristics, Management, and Outcomes of Difficult-to-Treat Inflammatory Bowel Disease. J Crohns Colitis. 2025;19(3):jjae145. doi:10.1093/ecco-jcc/jjae145
3. Bezzio C, Franchellucci G, Savarino EV, et al. Upadacitinib in Patients With Difficult-to-Treat Crohn's Disease [published correction appears in Crohns Colitis 360. 2025 Mar 25;7(1):otaf022. doi: 10.1093/crocol/otaf022.]. Crohns Colitis 360. 2024;6(4):otae060. Published 2024 Oct 24. doi:10.1093/crocol/otae060
4. Devi J, Xu A, Stone M, et al. Real-World Effectiveness and Safety of Upadacitinib in Crohn's Disease: A Multicenter Study. Clin Gastroenterol Hepatol. Published online March 8, 2025. doi:10.1016/j.cgh.2025.01.012