Introduction

Butyrate has shown anti-inflammatory effects and plays an important role in maintaining gut homeostasis, providing symptomatic relief when orally supplemented in patients suffering from various colonic diseases. In a previous pilot study, we demonstrated an important biologic effect of microencapsulated sodium butyrate (BLM) in patients with IBD(1).

Aims & Methods

In this randomised, double-blind, placebo-controlled study, 140 IBD patients in remission or with mild disease (n=60 Crohn's disease, CD and n=80 Ulcerative Colitis, UC) were randomized to oral administration of BLM/placebo for 3 months, in addition to conventional therapy. As primary aim we investigated the changes in microbiome composition induced by BLM treatment. Fecal microbiota from stool samples was assessed by 16S sequencing. Clinical disease activity assessed by using Harvey Bradshaw Index (HBI) for CD and partial-Mayo Score (pMS) for UC, quality of life assessed by using Inflammatory Bowel Disease Questionnaire 32 (IBDQ-32) and adherence-dietary-raccomandation were evaluated before and after treatment (T0=0 day and T1=90 days).

Results

Demographics and clinical characteristics were similar between the two populations. Moreover, they adhere to the recommendations of World Cancer Research Fund/American Institute for Cancer Research(WCRF-AIRC) regarding good and healthy nutrition(Table.1). After treatment of CD patients, the HBI score, dichotomized into remission and active disease, showed a significant improvement for those treated with BLM as compared to placebo (McNemar’s p=0.013 vs p>0.9). IBDQ-32 significantly improved in CD and UC, more markedly in the treatment group (CD: treat. 170/184 vs Pb. 188/196_95% CI 4.1,21 vs1.1,9.8;; UC: treat.185/195 vs Pb.188/188_95% CI 4.5,19 vs 2.8,7). The microbiota sequencing highlighted two different enterotype in CD population: the first one was characterized by Bacteroidota prevalence (with a genus prevalence of Fecalibacterium, Alistipes, and Roseburia). The second enterotype was characterized by Firmicutes prevalence (with a genus prevalence of Escherichia-Shigella and Lachnoclostridium). BLM had a more pronounced effect on the Bacteroidota enterotype where the taxa associated with intestinal comfort, SCFA production, and anti-obesity increased after treatment, while the taxa associated with CRC and intestinal inflammation, decreased. Finally, a significant separation was observed in samples from patients who have undergone minor surgery (ileo-colon), compared to non-surgery patients. The variable “surgery” seems to be associated with the Bacteroidota enterotype.

Conclusion

Sodium butyrate supplementation significantly improved clinical outcomes and quality of life in patients with CD. The subpopulation of patients undergoing ileo-colonic resection was microbiologically diversified compared to the non-surgery population. These results indicate that butyrate therapy may be more appropriate for the treatment of CD subjects with colonic preservation.

References

1. Facchin S, Vitulo N, Calgaro M, et al.. Microbiota changes induced by microencapsulated sodium butyrate in patients with inflammatory bowel disease. Neurogastroenterol Motil. 2020 Oct;32(10):e13914. doi: 10.1111/nmo.13914. Epub 2020 May 31. PMID: 32476236; PMCID: PMC7583468.

Disclosure

Sonia Facchin has received lecture or consultancy fees from SILA and Unifarco ; Edoardo Savarino has received lecture or consultancy fees from Abbvie, Amgen, Bristol-Myers Squibb, Fresenius Kabi, Grifols, Janssen, Johnson&Johnson, Innovamedica, Merck & Co, Novartis, Sandoz, Shire, SILA, Sofar, Takeda, Unifarco.

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

A high body mass index (BMI) may negatively impact treatment efficacy in patients with ulcerative colitis (UC) treated with advanced therapies, such as biologics,¹ which is relevant due to the prevalence of obesity and UC increasing substantially over the past decades.^2,3 Etrasimod is an oral, once-daily (QD), selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active UC.

Aims & Methods

This post hoc analysis of ELEVATE UC 52 and ELEVATE UC 12 investigated the impact of BMI on the efficacy and safety of etrasimod in patients with UC. ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369) were phase 3, randomised, placebo-controlled trials.⁴ ELEVATE UC 52 had a treat-through design consisting of a 12-week (wk) induction and 40-wk maintenance period; ELEVATE UC 12 comprised a 12-wk induction period. Patients who received ≥1 dose of etrasimod 2 mg QD or placebo were stratified by baseline BMI: <25 kg/m², 25–30 kg/m² and >30 kg/m². Efficacy outcomes (aligned to the predefined outcomes for the ELEVATE UC 52 and ELEVATE UC 12 trials) included the primary endpoint (clinical remission) and selected secondary endpoints at Wk 12 (data pooled for both trials) and Wk 52 (ELEVATE UC 52 only). Safety outcomes assessed the proportions of treatment-emergent adverse events (TEAEs).

Results

Of the 787 patients enrolled in the ELEVATE UC clinical programme, 443 (56.3%) had baseline BMI <25 kg/m², 217 (27.6%) had baseline BMI 25–30 kg/m² and 127 (16.1%) had baseline BMI >30 kg/m². In the BMI <25 kg/m² and BMI 25–30 kg/m² subgroups, significantly more patients (p<0.05) receiving etrasimod vs placebo achieved all efficacy endpoints at Wks 12 and 52. In the BMI >30 kg/m² subgroup, significantly more patients receiving etrasimod vs placebo achieved clinical remission at Wk 52 (p<0.0001; Wk 12: p=0.05), endoscopic improvement and clinical response at Wks 12 and 52, and corticosteroid-free clinical remission at Wk 52 (all p<0.05; Table). The proportions of patients with the most common TEAEs were generally consistent between BMI subgroups receiving etrasimod. Incidence of serious AEs was generally similar across BMI subgroups receiving etrasimod (<25 kg/m²: 17/308 [5.5%]; 25–30 kg/m²: 8/137 [5.8%]; >30 kg/m²: 1/82 [1.2%]).

Conclusion

In the ELEVATE UC clinical programme, significant improvements in efficacy were observed for patients receiving etrasimod 2 mg QD vs placebo, regardless of baseline BMI. The safety profile of etrasimod was consistent between BMI subgroups and with the overall ELEVATE UC population.

References

1. Kurnool S et al. Aliment Pharmacol Ther 2018; 47: 1472–1479.
2. Molodecky NA et al. Gastroenterology 2012; 142: 46-54 e42; quiz e30.
3. Ng M et al. Lancet 2014; 384: 766–781.
4. Sandborn WJ et al. J Crohns Colitis 2023; 17: 338–351.

Disclosure

AJY has received consultancy fees from AbbVie, Pfizer Inc, Arena, Takeda and Bristol Myers Squibb; and lecture/speaker fees from Bristol Myers Squibb. MDL is a consultant for AbbVie, Janssen, Pfizer Inc, Takeda, Bristol Myers Squibb, Target PharmaSolutions, Prometheus, Lilly, Salix, Valeant, Genentech, Roche, Calibr and Theravance; and has received research support from Pfizer Inc and Takeda. JT has received advisory board fees from AbbVie, Arena, Bristol Myers Squibb, Galapagos, Janssen and Pfizer Inc; research grants from AbbVie and Janssen; and speaker fees from AbbVie, Galapagos, Janssen and Pfizer Inc. NN is a consultant and advisory board member for AbbVie, Bristol Myers Squibb, Janssen, Lilly and Pfizer Inc; and has received research support from Ferring, Janssen, Pfizer Inc and Seres. RKC has received consultancy and advisory board fees from AbbVie, Adiso, Bristol Myers Squibb, CorEvitas, Fresenius Kabi, Fzata, IBD Education Group, Janssen, Magellan Health, Option Care, Pfizer Inc, Sandoz, Samsung Bioepis, Sebela and Takeda; and research grant/support from Janssen. AMA is an employee and shareholder of Pfizer Inc. DB and WN are employees of Pfizer Inc. CMC and JW are employees and shareholders of Pfizer Inc. GP is an employee of Pfizer Healthcare India Private Ltd. MG is an employee and shareholder of Pfizer AG. RP is a consultant for Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx and UCB; has received speaker fees for AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Lilly, Merck, Organon, Pfizer, Roche, Sandoz, Shire and Takeda; is an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda and Ventyx; and has received research support from AbbVie, Janssen, Takeda and Pfizer.

Introduction

Mirikizumab is a humanised, IgG4 monoclonal antibody directed against the p19 subunit of IL-23, a key inflammatory mediator in inflammatory bowel disease. Mirikizumab was superior to placebo in inducing clinical remission as well as other symptomatic, clinical, and endoscopic endpoints and had an acceptable safety profile in adults with moderately to severely active ulcerative colitis (UC) in the Phase (Ph)3 LUCENT-1 induction and the Ph3 LUCENT-2 maintenance studies. Here we report the first pharmacokinetic (PK), efficacy, and safety data in paediatric patients with moderately to severely active UC from the Ph2 SHINE-1 study (NCT04004611), following a 12-week induction period.

Aims & Methods

Children and adolescents aged 2 to <18 years old (n=26) with active UC as defined by a Modified Mayo Score (MMS) of 4-9 points and a centrally read Mayo endoscopic subscore ≥2 and who had an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies, or those with corticosteroid-dependent colitis were enrolled in the study. Patients weighing >40 kg received an induction dose of 300 mg via intravenous (IV) infusion and patients weighing ≤40 kg received 5 or 10 mg/kg via (IV) infusion at Weeks 0, 4, and 8. The primary endpoint evaluated the PK of mirikizumab treatment to confirm doses for Phase 3. Patients were assessed at Week 12 for clinical response, clinical remission, and endoscopic remission and were monitored for safety throughout the trial.

Results

For paediatric patients >40kg, the observed and PK model-estimated exposures were similar to adult levels. For paediatric patients ≤40kg, the exposure at 5 mg/kg matched the adult range based on both observed and modeled concentrations. Exposure at 10 mg/kg was ~2 fold higher than the adult mean. MMS clinical response and remission, and endoscopic remission rates were consistent with those of the LUCENT adults (Table 1); PUCAI response and remission rates were acceptable. The safety findings observed in the paediatric patients are consistent with the LUCENT-1 data.

Table 1. Week 12 Mirkizumab Phase 2 Peds UC Data (SHINE-1) Comparison to Mirikizumab Phase 3 Adult UC Data (LUCENT-1)

Conclusion

In this Ph2 paediatric UC study, mirikizumab demonstrated similar observed PK concentrations to those reported in the adult LUCENT-1 induction study, an acceptable safety profile, and clinically meaningful improvement in clinical response, clinical remission and endoscopic remission following induction treatment with mirikizumab. These results provide the first reported efficacy of a p19 inhibitor in paediatric patients with UC and provide the foundation for the pivotal Ph3 paediatric study.

Disclosure

J. L. Kaplan has nothing to disclose; A. Bousvaros has received research support from: AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Buhlmann Diagnostics, Eli Lilly and Company, Janssen, Procise Diagnostics, and Takeda; was a consultant for: Best Doctors, Eli Lilly and Company, Fresenius Kabi, and Takeda; and has received honoraria and royalties from: Boston University and UptoDate;
D. Turner has received consultation fees, research grants, royalties, and/or honoraria from: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring Pharmaceuticals, Janssen, Pfizer, Prometheus Biosciences, Roche, Shaare Zedek Medical Center, Shire, Sorriso Pharmaceuticals, Takeda, The Hospital for Sick Children, and Thermo Fisher Scientific; M. Dubinsky has received honoraria as a consultant for: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma; has been contracted for research by: AbbVie, Janssen, Pfizer, and Prometheus Biosciences; has stock interest in: Trellus Health; and has received licensing fees from: Takeda; W. J. Komocsar, A. Larkin, J. Johns, X. Zhang, C. Little, W. Crandall, and V. Arora are employees and shareholders of: Eli Lilly and Company; J. Hyams is on the advisory board for: Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, and Janssen; and was a consultant for: AbbVie, Pfizer, and Takeda

Introduction

Etrasimod is an oral, once-daily (QD), selective sphingosine 1‑phosphate (S1P)_1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). S1P receptor modulation reversibly sequesters specific lymphocyte subsets in lymph nodes.¹

Aims & Methods

This study aimed to better understand immune cell type selectivity of etrasimod using in-depth immunophenotyping of peripheral blood mononuclear cells (PBMC). In ELEVATE UC 52 (NCT03945188) and ELEVATE UC 12 (NCT03996369), patients (pts) aged 16–80 years with moderately to severely active UC were randomised 2:1 to etrasimod 2 mg QD or placebo (PBO). PBMCs were collected and characterised using flow cytometry and epigenetic immune monitoring by Epiontis ID for baseline and Week 12 assessments (both trials). Outputs were expressed as mean percent change from baseline (%CFB) of cell frequencies. Statistical tests were performed with t-tests at a nominal significance level of 0.05.

Results

In ELEVATE UC 52 and ELEVATE UC 12, 185 (64.0%) and 120 (50.4%) pts receiving etrasimod 2 mg QD, and 98 (68.1%) and 68 (58.6%) receiving PBO, respectively, were included in the biomarker analysis set. Baseline demographics and disease characteristics were similar to the full analysis set. Using flow cytometry, in both trials, %CFB reductions were observed in total T and B cells with etrasimod (62.24–72.46% decrease) but not PBO. Among CD4+ T cell subsets, the greatest %CFB reductions with etrasimod were for naïve (Tn) cells. Reductions were also seen in central memory (Tcm), helper (Th)2, regulatory, Th1, Th17 and effector memory (Tem) cells (61.00–87.07% decrease) in both trials. Similarly, CD8+ Tn and Tcm subsets were reduced (69.33–78.48% decrease) with etrasimod; minimal changes were seen in CD8+ Tem cells. For B cell subsets, memory cells and naïve cells were reduced with etrasimod in both trials (62.45–78.03% decrease). In both trials, minimal changes were observed for natural killer cells. With Epiontis ID, etrasimod induced significant reductions in peripheral CD3+, CD4+, GATA3+, IL17A+, FOXP3+, CCR7+ and LRP5A+ cells vs PBO (both trials; Table).

Conclusion

Etrasimod induces selective, pharmacodynamic changes in certain PBMC subsets. Results of cell-type characterisation by flow cytometry and Epiontis ID were complementary.

References

1. Scott FL et al. Br J Pharmacol 2016; 173: 1778–1792

Disclosure

BS has received lecture fees from AbbVie, CED Service GmbH, Chiesi, Falk, Forga Software, Galapagos, IBD Passport, Janssen, Materia Prima, Pfizer Inc and Lilly; consultancy fees from AbbVie, Arena Pharma, Boehringer Ingelheim, BMS, Celgene, CT-Scout, Endpoint Health, Galpagos, Gilead Sciences, Janssen, Landos, Lilly, Pfizer Inc, PredictImmune and PsiCro. CMC, XG and JCW are employees and shareholders of Pfizer Inc. RDR is an employee of and holds stock options with Pfizer Inc. MTA has received consultancy fees from AbbVie Inc, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celsius, Eli Lilly, Gilead, Janssen, Janssen Biotech Inc, Microba Life Sciences, Pfizer, Prometheus, Prometheus Bioscience, Takeda, and UCB Biopharma. SV has received lecture/speaker fees from AbbVie, Dr. Falk Pharma, Ferring, Galapagos, Hospira, Janssen, MSD, Takeda and Tillotts; consultancy/advisory fees from AbbVie, AbolerIS Pharma, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Dr Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson and Johnson, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillots Pharma AG and Zealand Pharma; grant/research support from AbbVie, MSD, Pfizer Inc, Galapagos, Janssen and Takeda. ID has received consultancy fees, research grants or honoraria from Abbott, AbbVie, Altman, Arena, Athos, Cambridge Healthcare, Celgene/BMS, Celltrion, Falk Pharma, DSM, Ferring, Food Industries Organisation, Galapagos, Genentech/Roche, Gilead, GSK, Hospital for Sick Children, Integra Holdings, Iterative Scopes, Janssen, Mediahuset, Medscape, Neopharm, Nestle, Peer voice, Pfizer, Rafa Laboratories, Sangamo, Sublimity, Takeda and Wilbio. KMR has received grant/research support from Bristol Myers Squibb. HKK has received consultancy fees from Kinevant Sciences and is an employee/shareholder for Uniquity Bio. MG is an employee and shareholder of Pfizer AG. SD has received lecture/speaker fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer and Takeda; consultancy/advisory fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead Sciences, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer Inc, Roche, Sandoz, Takeda, TiGenix, UCB, and Vifor; holds directorship/ownership for Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele.

Clinical Case Summary

A 78-year-old patient with known non-ischaemic dilated cardiomyopathy with reduced left ventricular ejection fraction, asthma and type 2 diabetes mellitus was treated with amiodarone from 2019. In April 2023, he developed hypersensitivity pneumonitis due to amiodarone and methylprednisolone (0.5 mg/kg body weight) was initiated along with prophylactic osteoporosis treatment and trimethoprim with sulphamethoxazole. On the 18th day of methylprednisolone treatment, an Addisonian crisis resulted from acute gastroenteritis. Subsequent investigations revealed Herpes simplex virus type 1 infection and elevated serum Cytomegalovirus (CMV) DNA levels. Gastrointestinal complications included fungal esophagitis, Helicobacter pylori chronic gastritis and mild chronic duodenitis. Ischemic colitis and coeliac disease was ruled out. Despite negative findings for inflammatory bowel disease and parasitic infections, CMV infection was histologically confirmed in the terminal ileum and colonic mucosa samples. Abdominal CT confirmed infectious enteritis involving the entire small bowel. Treatment with valganciclovir (900 mg BID) for six weeks was successful, leading to clinical improvement and a disappearance of CMV DNA. Follow-up endoscopic and histological examinations did not confirm the persistence of CMV infection. Regular follow-ups with a cardiologist and a pulmonologist continue, with the patient still receiving low-dose methylprednisolone. Further hematological evaluation is planned due to persistent monoclonal gammopathy, however until now we didn't proof lymphoma, myeloma or other hematological malignancy.
The case underscores the challenges in managing CMV infections in non-traditionally immunocompromised patients, necessitating vigilance in diagnosis and treatment despite limited reported cases in the literature.

References

Reference Illustrative material:

• Table of patient laboratory findings
• Endoscopic image of CMV ulcer in terminal ileum
• Histological image of CMV infection in terminal ileum

Introduction

Increased blood pressure (BP) and hypertension are known adverse effects of sphingosine 1-phosphate (S1P)_1,4,5 receptor modulators. Etrasimod is an investigational, oral, once-daily, selective S1P_1,4,5 receptor modulator in development for the treatment of moderately to severely active ulcerative colitis (UC).

Aims & Methods

We assessed the impact of etrasimod on BP and hypertension development among patients (pts) in the etrasimod UC clinical programme. Pivotal (placebo [PBO]-controlled phase [p]3 [NCT03945188; NCT03996369] studies) and All UC (PBO-controlled plus open-label extension [OLE]; p2 [NCT02447302], p3 and OLE [NCT03950232 and NCT04176588, data snapshot Jan 31, 2022; NCT02536404] studies) cohort data were analysed. BP was assessed at each visit and at 2 and 4 weeks (wks) post‑treatment cessation. Proportions and exposure-adjusted incidence rates (EAIRs; pts with AEs divided by the total pt‑years [PY] at risk for AEs, per 1 PY) of treatment‑emergent Hypertension (Medical Dictionary for Regulatory Activities preferred term [PT]) AEs among pts receiving etrasimod (2 mg once daily; both cohorts) or PBO (Pivotal UC cohort) were assessed. Characteristics of pts with Hypertension AEs that met sponsor-designated events of interest (SDEI) criteria (related to hypertension associated with sustained increases in BP [systolic/diastolic: ≥ 160/100 mmHg], or requiring new or increased antihypertensive therapy) were analysed descriptively.

Results

In the Pivotal and All UC cohorts, 11/527 (2.1%; EAIR, 0.04; PBO: 2/260 [0.8%; EAIR, 0.02]) and 20/942 (2.1%; EAIR, 0.03) etrasimod-treated pts had PT Hypertension, respectively; none led to study treatment discontinuation. In the All UC cohort, 19/942 (2.0%; EAIR, 0.02) etrasimod-treated pts had hypertension-related SDEIs. Of these events, 6 were in pts with hypertension history; none were serious or led to treatment discontinuation; 6 resolved (5 with intervention), 8 were resolving/unknown outcome and 5 were unresolved. Etrasimod‑treated pts had minimal changes in BP over time (All UC cohort, mean change in systolic/diastolic BP at Wk52: 2.9/1.2 mmHg, respectively; Table). In the All UC cohort, at Wk104, no etrasimod-treated pts had a systolic/diastolic BP > 160/100 mmHg, respectively.

Conclusion

Hypertension events were infrequent among etrasimod-treated pts. No clinically meaningful changes in BP with etrasimod 2 mg over time or following treatment discontinuation were observed up to 2 years. Data interpretations are limited by small pt numbers.

Disclosure

SV: lecture/speaker fees: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Hospira, MSD, Takeda, Tillotts; consultancy/advisory fees: AbbVie, AbolerIS, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, Hospira, Imidomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer Inc, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance Biopharma, Tillotts, Zealand Pharma; grant/research support: AbbVie, MSD, Pfizer Inc, Galapagos, Takeda.
DTR: grant support: Takeda, Helmsley Charitable Trust and GastroIntestinal Research Foundation; consultancy fees/advisory boards: AbbVie, AltruBio, ASLAN Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Chronicles, Syneos, ClostraBio, Connect Biopharma, EcoR1, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido Biosciences, Eli Lilly, Pfizer, Prometheus, Reistone, Seres Therapeutics, Takeda, Target RWE, Trellus Health; Board of Trustees: Crohn’s & Colitis Foundation and Cornerstones Health, Inc; stock options: Alike Health, AltruBio, Datos Health, Iterative Health.
LP-B: grant/research support: Takeda, Fresenius Kabi, Celltrion; lecture/speaker fees: Galapagos, AbbVie, Janssen, Genentech, Ferring Pharmaceuticals, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena Pharmaceuticals, Lilly, Gilead Sciences, Viatris, Medac, Sanofi; consultancy fees: AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Biogen, Bristol-Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki Pharma, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; stockholder: CTMA.
MCD: consultancy fees: AbbVie, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead Sciences, Janssen Pharmaceuticals, Pfizer Inc, Prometheus Laboratories, Takeda, Trellus Health, UCB; grant/research support: Janssen; shares/royalties: Trellus Health; directorship/ownership interests: Trellus Health.
MR: Unrestricted Educational Grants: Abbvie, BMS, Janssen, UCB, Pfizer, Takeda, Celgene, Genentech, Gilead; advisory boards/Consultant: Abbvie, Janssen, UCB, Takeda, Pfizer, Miraca Labs, Amgen, Celgene, Seres, Allergan, Genentech, Gilead, Salix, Prometheus, Lilly, TARGET Pharma Solutions, ALFASIGMA, S.p.A., Bristol-Myers Squibb (BMS), CME Companies: CME Outfitters, Imedex, GI Health Foundation (GiHF), Cornerstones, Remedy, MJH life sciences; royalties: Wolters Kluwer Health: Author/Editor of UpToDate.
PMI: grant support: Celltrion, Janssen, MSD, Takeda; lecture fees: AbbVie, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, MSD, Janssen, Pfizer, Takeda, Tillotts, Sapphire Medical, Sandoz, Shire, Warner Chilcott; advisory fees: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Genentech, Gilead Sciences, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor, Warner Chilcott.
MG and KL: employees & shareholders of Pfizer AG.
JW, IM, JCW, CR: employees & shareholders of Pfizer Inc.
AM: employee of Pfizer Ltd and shareholder of Pfizer Inc.
AY: consultancy fees: Pfizer, Arena Pharmaceuticals, Takeda, Bristol-Myers Squibb; lecture/speaker fees: Bristol-Myers Squibb.