Safety and efficacy of ontamalimab in inflammatory bowel disease: A systematic review and dose- response meta-analysis
Abstract
Inflammatory bowel diseases (IBDs), such as Crohn’s disease and ulcerative colitis, involve chronic inflammation of the digestive tract. The incidence of IBD has been increasing globally, posing a growing burden despite advancements in treatment. Novel therapies targeting adhesion molecules such as MAdCAM-1 show promise by specifically inhibiting lymphocyte infiltration into the gut, potentially offering safer and more effective treatment options. This meta-analysis and systematic review were conducted to provide efficacy and safety analysis of ontamalimab for IBD treatment. Dose-response (DRMA), network (NMA), and random effect meta-analysis were conducted to extract clinical response, clinical remission, biomarker change, and adverse events of ontamalimab. Studies were retrieved from PubMed, Cochrane, and EMBASE to describe the pooled risk ratio (RR) and heterogeneity was determined if I2 >50%. RoB2 tool and ROBINS-I were used to assess risk of bias in RCT and clinical trial studies, respectively. The result was considered significant if p<0.05. A total of 670 studies were screened, resulting in 8 multicentre studies. There were significant differences in clinical response (RR: 1.39; 95%CI: 1.12–1.73; p = 0.003; I2= 35%), clinical remission (RR: 1.72; 95%CI: 1.17–2.53; p=0.006; I2= 26%), mean change of FC (RR: 624.29; 95%CI: 543.28-705.29; p<0.001; I2= 0%), mean change of CRP serum (RR: 9.71; 95%CI: 7.12–12.3; p<0.001), and mean MAdCAM-1 serum level (RR: 235.57; 95%CI: 203.80–267.33; p <0.001) between ontamalimab 75 mg and placebo after 12 wk of treatment. Meanwhile, adverse events from both groups were similar to those observed in patients treated with either placebo or ontamalimab. This study concluded that ontamalimab 75mg demonstrated significant efficacy in treating IBD, achieving superior outcomes in clinical response and clinical remission compared to placebo. Importantly, no cases of PML and significant adverse events were detected, indicating a favorable safety profile relative to other anti-MAdCAM-1 therapies.
References
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411(6837):603-6.
https://doi.org/10.1038/35079114
Wang R, Li Z, Liu S, Zhang D. Global, regional and national burden of inflammatory bowel disease in 204 countries and territories from 1990 to 2019: a systematic analysis based on the Global Burden of Disease Study 2019. BMJ 2023; 13(3):e065186.
https://doi.org/10.1136/bmjopen-2022-065186
Dharni K, Singh A, Sharma S, Midha V, Kaur K, Mahajan R, et al. Trends of inflammatory bowel disease from the Global Burden of Disease Study (1990-2019). Indian J Gastroenterol 2024; 43(1):188-98.
https://doi.org/10.1007/s12664-023-01430-z
Daniella D, Simkoputera J, Wiguna C. Inflammatory bowel disease in young adult. Indones J Gastroenterol Hepatol Dig Endosc 2020; 20(1):58-62.
https://doi.org/10.24871/201201958-62
Erle DJ, Briskin MJ, Butcher EC, Garcia-Pardo A, Lazarovits AI, Tidswell M. Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. J Immunol 1994; 153(2):517-28.
https://doi.org/10.4049/jimmunol.153.2.517
Steffen BJ, Breier G, Butcher EC, Schulz M, Engelhardt B. ICAM-1, VCAM-1, and MAdCAM-1 are expressed on choroid plexus epithelium but not endothelium and mediate binding of lymphocytes in vitro. Am J Pathol 1996; 148(6):1819-38.
Liaskou E, Karikoski M, Reynolds GM, Lalor PF, Weston CJ, Pullen N, et al. Regulation of mucosal addressin cell adhesion molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase activity. Hepatology 2011; 53(2):661-72.
https://doi.org/10.1002/hep.24085
Briskin M, Winsor-Hines D, Shyjan A, Cochran N, Bloom S, Wilson J, et al. Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 1997; 151(1):97-110.
Pullen N, Molloy E, Carter D, Syntin P, Clemo F, Finco-Kent D, et al. Pharmacological characterization of PF-00547659, an anti-human MAdCAM monoclonal antibody. Br J Pharmacol 2009; 157(2):281-93.
https://doi.org/10.1111/j.1476-5381.2009.00137.x
Chu X, Biao Y, Liu C, Zhang Y, Liu C, Ma J, et al. Network meta-analysis on efficacy and safety of different biologics for ulcerative colitis. BMC Gastroenterol 2023; 23(1):346.
https://doi.org/10.1186/s12876-023-02938-6
Vermeire S, Ghosh S, Panes J, Dahlerup JF, Luegering A, Sirotiakova J, et al. The mucosal addressin cell adhesion molecule antibody PF-00547,659 in ulcerative colitis: a randomised study. Gut 2011; 60(8):1068-75.
https://doi.org/10.1136/gut.2010.226548
Saruta M, Park D Il, Kim Y-H, Yang S-K, Jang B-I, Cheon JH, et al. Anti-MAdCAM-1 antibody (PF-00547659) for active refractory Crohn's disease in Japanese and Korean patients: the OPERA study. Intest Res 2020; 18(1):45-5.
https://doi.org/10.5217/ir.2019.00039
Vermeire S, Sandborn WJ, Danese S, Hébuterne X, Salzberg BA, Klopocka M, et al. Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 2017; 390(10090):135-44.
https://doi.org/10.1016/S0140-6736(17)30930-3
Sandborn WJ, Lee SD, Tarabar D, Louis E, Klopocka M, Klaus J, et al. Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study. Gut 2018; 67(10):1824-35.
https://doi.org/10.1136/gutjnl-2016-313457
Reinisch W, Sandborn WJ, Danese S, Hébuterne X, Kłopocka M, Tarabar D, et al. Long-term safety and efficacy of the anti-MAdCAM-1 monoclonal antibody ontamalimab [SHP647] for the treatment of ulcerative colitis: the open-label study TURANDOT II. J Crohn's colitis 2021; 15(6):938-49.
https://doi.org/10.1093/ecco-jcc/jjab023
Awad AA, Aboelkhier MM, Mohamed RG, Abbas AW, Hageen AW, Alnomani YR, et al. Efficacy and safety of ontamalimab in treating inflammatory bowel disease: a systematic review and meta-analysis of randomized controlled trials. Curr Rharmacol Reports 2024; 10(6):467-84.
https://doi.org/10.1007/s40495-024-00363-1
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366:l4898.
https://doi.org/10.1136/bmj.l4898
Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016; i4919.
https://doi.org/10.1136/bmj.i4919
Greenland S, Longnecker MP. Methods for trend estimation from summarized dose-response data, with applications to meta-analysis. Am J Epidemiol 1992; 135(11):1301-9.
https://doi.org/10.1093/oxfordjournals.aje.a116237
D'Haens GR, Reinisch W, Lee SD, Tarabar D, Louis E, Kłopocka M, et al. Long-term safety and efficacy of the anti-mucosal addressin cell adhesion molecule-1 monoclonal antibody ontamalimab (SHP647) for the treatment of Crohn's disease: the OPERA II study. Inflamm Bowel Dis 2022; 28(7):1034-44.
https://doi.org/10.1093/ibd/izab215
Vermeire S, Danese S, Sandborn WJ, Schreiber S, Hanauer S, D'Haens G, et al. Efficacy and safety of the anti-mucosal addressin cell adhesion molecule-1 antibody ontamalimab in patients with moderate-to-severe ulcerative colitis or Crohn's disease. J Crohn's Colitis 2024; 18(5):708-19.
https://doi.org/10.1093/ecco-jcc/jjad199
D'Haens G, Vermeire S, Vogelsang H, Allez M, Desreumaux P, Van Gossum A, et al. Effect of PF-00547659 on central nervous system immune surveillance and circulating β7+ T cells in Crohn's disease: Report of the TOSCA study. J Crohn's Colitis 2018; 12(2):188-96.
https://doi.org/10.1093/ecco-jcc/jjx128
Nelson SM, Nguyen TM, McDonald JW, MacDonald JK. Natalizumab for induction of remission in Crohn's disease. Cochrane database Syst Rev 2018; 8(8):CD006097.
