Inebilizumab for Treatment of IgG4-Related Disease

John H Stone; Arezou Khosroshahi; Wen Zhang; Emanuel Della Torre; Kazuichi Okazaki; Yoshiya Tanaka; J Matthias Löhr; Nicolas Schleinitz; Lingli Dong; Hisanori Umehara; Marco Lanzillotta; Zachary S Wallace; Mikael Ebbo; George J Webster; Fernando Martinez Valle; Manu K Nayar; Cory A Perugino; Vinciane Rebours; Xinxin Dong; Yanping Wu; Qing Li; Nishi Rampal; Daniel Cimbora; Emma L Culver; MITIGATE Trial Investigators

doi:10.1056/NEJMoa2409712

Inebilizumab for Treatment of IgG4-Related Disease

N Engl J Med. 2024 Nov 14. doi: 10.1056/NEJMoa2409712. Online ahead of print.

Authors

John H Stone¹, Arezou Khosroshahi¹, Wen Zhang¹, Emanuel Della Torre¹, Kazuichi Okazaki¹, Yoshiya Tanaka¹, J Matthias Löhr¹, Nicolas Schleinitz¹, Lingli Dong¹, Hisanori Umehara¹, Marco Lanzillotta¹, Zachary S Wallace¹, Mikael Ebbo¹, George J Webster¹, Fernando Martinez Valle¹, Manu K Nayar¹, Cory A Perugino¹, Vinciane Rebours¹, Xinxin Dong¹, Yanping Wu¹, Qing Li¹, Nishi Rampal¹, Daniel Cimbora¹, Emma L Culver¹; MITIGATE Trial Investigators

Affiliation

¹ From the Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston (J.H.S., Z.S.W., C.A.P.); the Division of Rheumatology, Emory University School of Medicine, Atlanta (A.K.); the Department of Rheumatology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing (W.Z.), and the Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan (L.D.) - both in China; the Unit of Immunology, Rheumatology, Allergy, and Rare Diseases, IRCCS San Raffaele Scientific Institute, Milan (E.D.T., M.L.); the Department of Internal Medicine, Kansai Medical University Kori Hospital, Osaka (K.O.), the First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu (Y.T.), and Nagahama City Hospital, Nagahama (H.U.) - all in Japan; the Department of Clinical Science, Intervention, and Technology, Karolinska Institutet, Stockholm (J.M.L.); Aix-Marseille Université, Assistance Publique-Hôpitaux de Marseille, Centre National de la Recherche Scientifique, INSERM, Centre d'Immunologie de Marseille-Luminy, Hopital de la Timone, Internal Medicine Department, Marseille (N.S., M.E.), and the Pancreatology and Digestive Oncology Department, Beaujon Hospital, Université Paris Cité, Clichy (V.R.) - both in France; the Department of Gastroenterology, University College London Hospitals, London (G.J.W.), the Hepato-Pancreato-Biliary Unit, Freeman Hospital, Newcastle upon Tyne (M.K.N.), and the Translational Gastroenterology and Liver Unit, John Radcliffe Hospital, and Nuffield Department of Medicine, University of Oxford, Oxford (E.L.C.) - all in the United Kingdom; the Internal Medicine Department, Vall d'Hebron Hospital, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona (F.M.V.); and Amgen, Thousand Oaks, CA (X.D., Y.W., Q.L., N.R., D.C.).

PMID: 39541094
DOI: 10.1056/NEJMoa2409712

Abstract

Background: IgG4-related disease is a multiorgan, relapsing, fibroinflammatory, immune-mediated disorder with no approved therapy. Inebilizumab targets and depletes CD19+ B cells and may be effective for treating patients with IgG4-related disease.

Methods: In this phase 3, multicenter, double-blind, randomized, placebo-controlled trial, adults with active IgG4-related disease underwent randomization in a 1:1 ratio to receive inebilizumab (300-mg intravenous infusions on days 1 and 15 and week 26) or placebo for a 52-week treatment period. Participants in both groups received identical glucocorticoid tapers. Glucocorticoids were allowed to treat disease flares, but background immunosuppressants were not permitted. The primary end point was the first treated, adjudicated disease flare during the treatment period, assessed in a time-to-event analysis. Key secondary end points were the annualized flare rate and treatment-free and glucocorticoid-free complete remission.

Results: A total of 135 participants with IgG4-related disease underwent randomization: 68 participants were assigned to receive inebilizumab and 67 were assigned to receive placebo. Treatment with inebilizumab reduced flare risk; 7 participants (10%) in the inebilizumab group had at least one flare, as compared with 40 participants (60%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.06 to 0.28; P<0.001). The annualized flare rate was lower with inebilizumab than with placebo (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). More participants in the inebilizumab group than in the placebo group had flare-free, treatment-free complete remission (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001) and flare-free, glucocorticoid-free complete remission (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001). Serious adverse events occurred during the treatment period in 12 of the participants (18%) who received inebilizumab and 6 of the participants (9%) who received placebo.

Conclusions: Inebilizumab reduced the risk of flares of IgG4-related disease and increased the likelihood of flare-free complete remission at 1 year, confirming the role of CD19-targeted B-cell depletion as a potential treatment for IgG4-related disease. (Funded by Amgen; MITIGATE ClinicalTrials.gov number, NCT04540497.).

Associated data

ClinicalTrials.gov/NCT04540497

Grants and funding

Not applicable/Amgen Foundation