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

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

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.