Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis
David Jayne, Brad Rovin, Eduardo F Mysler, Richard A Furie, Frederic A Houssiau, Teodora Trasieva, Jacob Knagenhjelm, Erik Schwetje, Yen Lin Chia, Raj Tummala, Catharina Lindholm, David Jayne, Brad Rovin, Eduardo F Mysler, Richard A Furie, Frederic A Houssiau, Teodora Trasieva, Jacob Knagenhjelm, Erik Schwetje, Yen Lin Chia, Raj Tummala, Catharina Lindholm
Abstract
Objective: To assess the efficacy and safety of the type I interferon receptor antibody, anifrolumab, in patients with active, biopsy-proven, Class III/IV lupus nephritis.
Methods: This phase II double-blinded study randomised 147 patients (1:1:1) to receive monthly intravenous anifrolumab basic regimen (BR, 300 mg), intensified regimen (IR, 900 mg ×3, 300 mg thereafter) or placebo, alongside standard therapy (oral glucocorticoids, mycophenolate mofetil). The primary endpoint was change in baseline 24-hour urine protein-creatinine ratio (UPCR) at week (W) 52 for combined anifrolumab versus placebo groups. The secondary endpoint was complete renal response (CRR) at W52. Exploratory endpoints included more stringent CRR definitions and sustained glucocorticoid reductions (≤7.5 mg/day, W24-52). Safety was analysed descriptively.
Results: Patients received anifrolumab BR (n=45), IR (n=51), or placebo (n=49). At W52, 24-hour UPCR improved by 69% and 70% for combined anifrolumab and placebo groups, respectively (geometric mean ratio=1.03; 95% CI 0.62 to 1.71; p=0.905). Serum concentrations were higher with anifrolumab IR versus anifrolumab BR, which provided suboptimal exposure. Numerically more patients treated with anifrolumab IR vs placebo attained CRR (45.5% vs 31.1%), CRR with UPCR ≤0.5 mg/mg (40.9% vs 26.7%), CRR with inactive urinary sediment (40.9% vs 13.3%) and sustained glucocorticoid reductions (55.6% vs 33.3%). Incidence of herpes zoster was higher with combined anifrolumab vs placebo (16.7% vs 8.2%). Incidence of serious adverse events was similar across groups.
Conclusion: Although the primary endpoint was not met, anifrolumab IR was associated with numerical improvements over placebo across endpoints, including CRR, in patients with active lupus nephritis.
Trial registration number: NCT02547922.
Keywords: autoimmune diseases; biological therapy; immune system diseases; lupus erythematosus; lupus nephritis; systemic.
Conflict of interest statement
Competing interests: DJ received grants or contracts from GlaxoSmithKline, consultancy fees from AstraZeneca, Boehringer-Ingelheim, Chemocentryx, GlaxoSmithKline, Novartis, Roche, Takeda and Vifor, speaker fees from Amgen, GlaxoSmithKline and Vifor, and owns stocks in Aurinia. BR received consulting fees from Aurinia, AstraZeneca, Calliditas, Tavere, Novartis, Omeros, Chemocentryx, Morphosys, Bristol Myers Squibb, and Janssen. EM received consulting fees from Pfizer, AbbVie, GlaxoSmithKline, Sandoz, Eli Lilly, Bristol Myers Squibb and AstraZeneca, speaking fees from Pfizer, Amgen, AbbVie, Eli Lilly and Roche, and honoraria from Pfizer, AbbVie and Eli Lilly. RAF received consulting fees, payment or honoraria, and support for attending meetings and/or travel from AstraZeneca, and has participated on a Data Safety Monitoring Board or Advisory Board for AstraZeneca. FAH has received grants and consulting fees from and has participated on a Data Safety Monitoring Board or Advisory Board for GlaxoSmithKline, and has received consulting fees from Idorsia. TT, JK, ES, RT and CL are employees of and own shares of AstraZeneca. YLC is a former employee of and owns shares of AstraZeneca and a current employee of Seagen.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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References
- Fava A, Petri M. Systemic lupus erythematosus: diagnosis and clinical management. J Autoimmun 2019;96:1–13. 10.1016/j.jaut.2018.11.001
- Hanly JG, O'Keeffe AG, Su L, et al. . The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology 2016;55:252–62. 10.1093/rheumatology/kev311
- Weening JJ, D'Agati VD, Schwartz MM, et al. . The classification of glomerulonephritis in systemic lupus erythematosus revisited. Kidney Int 2004;65:521–30. 10.1111/j.1523-1755.2004.00443.x
- Maroz N, Segal MS. Lupus nephritis and end-stage kidney disease. Am J Med Sci 2013;346:319–23. 10.1097/MAJ.0b013e31827f4ee3
- Wang H, Ren Y-le, Chang J, et al. . A systematic review and meta-analysis of prevalence of biopsy-proven lupus nephritis. Arch Rheumatol 2018;33:17–25. 10.5606/ArchRheumatol.2017.6127
- Tektonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1971-2015: a systematic review and Bayesian meta-analysis. Arthritis Rheumatol 2016;68:1432–41. 10.1002/art.39594
- Arriens C. Abstract number 1914. Abstract supplement 2019 ACR/ARP annual meeting. Arthritis Rheumatol 2019;71:1–5420.
- Feng X, Wu H, Grossman JM, et al. . Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum 2006;54:2951–62. 10.1002/art.22044
- Der E, Suryawanshi H, Morozov P, et al. . Tubular cell and keratinocyte single-cell transcriptomics applied to lupus nephritis reveal type I IFN and fibrosis relevant pathways. Nat Immunol 2019;20:915–27. 10.1038/s41590-019-0386-1
- Furie R, Khamashta M, Merrill JT, et al. . Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol 2017;69:376–86. 10.1002/art.39962
- Morand EF, Furie R, Tanaka Y, et al. . Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med 2020;382:211–21. 10.1056/NEJMoa1912196
- Furie RA, Morand EF, Bruce IN, et al. . Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol 2019;1:e208–19. 10.1016/S2665-9913(19)30076-1
- Hochberg MC. Updating the American College of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997;40:40. 10.1002/art.1780400928
- Yao Y, Higgs BW, Richman L, et al. . Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNα antibody, in systemic lupus erythematosus. Arthritis Res Ther 2010;12(Suppl 1):S6. 10.1186/ar2887
- Gladman DD, Ibañez D, Urowitz MB. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002;29:288–91.
- Petri M, Genovese M, Engle E, et al. . Definition, incidence, and clinical description of flare in systemic lupus erythematosus. A prospective cohort study. Arthritis Rheum 1991;34:937–44. 10.1002/art.1780340802
- Liang MH, Socher SA, Larson MG, et al. . Reliability and validity of six systems for the clinical assessment of disease activity in systemic lupus erythematosus. Arthritis Rheum 1989;32:1107–18. 10.1002/anr.1780320909
- Yao Y, Higgs BW, Morehouse C, et al. . Development of potential pharmacodynamic and diagnostic markers for anti-IFN-α monoclonal antibody trials in systemic lupus erythematosus. Hum Genomics Proteomics 2009;2009:374312. 10.4061/2009/374312
- Fanouriakis A, Kostopoulou M, Cheema K, et al. . 2019 update of the joint European League against rheumatism and European renal Association-European dialysis and transplant association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis 2020;79:713–23. 10.1136/annrheumdis-2020-216924
- Morales E, Galindo M, Trujillo H, et al. . Update on lupus nephritis: looking for a new vision. Nephron 2021;145:1–13. 10.1159/000511268
- Kuruvilla DMT, Tummala R, Roskos L. Characterization of the nonlinear pharmacokinetics and time-varying clearance of anifrolumab in patients with active systemic lupus erythematosus. American Association of Pharmaceutical Scientists (AAPS) PharmSci 2020;360.
- Rovin BH, Solomons N, Pendergraft WF, et al. . A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis. Kidney Int 2019;95:219–31. 10.1016/j.kint.2018.08.025
- Furie R, Rovin BH, Houssiau F, et al. . Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med 2020;383:1117–28. 10.1056/NEJMoa2001180
- Arriens C, Polyakova S, Adzerikho I, et al. . OP0277 Aurora phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis (LN). Ann Rheum Dis 2020;79:172.2–3. 10.1136/annrheumdis-2020-eular.5010
- Ugarte A, Danza A, Ruiz-Irastorza G. Glucocorticoids and antimalarials in systemic lupus erythematosus: an update and future directions. Curr Opin Rheumatol 2018;30:482–9. 10.1097/BOR.0000000000000527
- Lin Chia Y, Santiago L, Wang B, et al. . Exposure-response analysis for selection of optimal dosage regimen of anifrolumab in patients with systemic lupus erythematosus. Rheumatology 2021:keab176. 10.1093/rheumatology/keab176
- Gorriz JL, Martinez-Castelao A. Proteinuria: detection and role in native renal disease progression. Transplant Rev 2012;26:3–13. 10.1016/j.trre.2011.10.002
- Kostopoulou M, Fanouriakis A, Cheema K, et al. . Management of lupus nephritis: a systematic literature review Informing the 2019 update of the joint EULAR and European renal Association-European dialysis and transplant association (EULAR/ERA-EDTA) recommendations. RMD Open 2020;6:e001263. 10.1136/rmdopen-2020-001263
- Ugolini-Lopes MR, Seguro LPC, Castro MXF, et al. . Early proteinuria response: a valid real-life situation predictor of long-term lupus renal outcome in an ethnically diverse group with severe biopsy-proven nephritis? Lupus Sci Med 2017;4:e000213. 10.1136/lupus-2017-000213
- Anders H-J, Saxena R, Zhao M-H, et al. . Lupus nephritis. Nat Rev Dis Primers 2020;6:7. 10.1038/s41572-019-0141-9
- Modification of Diet in Renal Disease Study Group . The modification of diet in renal disease study: design, methods, and results from the feasibility study. Am J Kidney Dis 1992;20:18–33. 10.1016/S0272-6386(12)80313-1
- Corapi KM, Dooley MA, Pendergraft WF. Comparison and evaluation of lupus nephritis response criteria in lupus activity indices and clinical trials. Arthritis Res Ther 2015;17:110. 10.1186/s13075-015-0621-6
- Anders H-J, Jayne DRW, Rovin BH. Hurdles to the introduction of new therapies for immune-mediated kidney diseases. Nat Rev Nephrol 2016;12:205–16. 10.1038/nrneph.2015.206
- Moreno JA, Sevillano Ángel, Gutiérrez E, et al. . Glomerular hematuria: cause or consequence of renal inflammation? Int J Mol Sci 2019;20:2205. 10.3390/ijms20092205
- Tummala R, Abreu G, Pineda L, et al. . Safety profile of anifrolumab in patients with active SLE: an integrated analysis of phase II and III trials. Lupus Sci Med 2021;8:e000464. 10.1136/lupus-2020-000464
- Kang T-Y, Lee H-S, Kim T-H, et al. . Clinical and genetic risk factors of herpes zoster in patients with systemic lupus erythematosus. Rheumatol Int 2005;25:97–102. 10.1007/s00296-003-0403-3
- Mok CC, Tse SM, Chan KL, et al. . Prevalence and risk factors of herpes zoster infection in patients with biopsy proven lupus nephritis undergoing immunosuppressive therapies. Lupus 2020;29:836–44. 10.1177/0961203320923739
- Jung J-Y, Yoon D, Choi Y, et al. . Associated clinical factors for serious infections in patients with systemic lupus erythematosus. Sci Rep 2019;9:9704. 10.1038/s41598-019-46039-5
- Singh JA, Hossain A, Kotb A, et al. . Treatments for lupus nephritis: a systematic review and network metaanalysis. J Rheumatol 2016;43:1801–15. 10.3899/jrheum.160041
- Food and Drug Administration . SAPHNELO (anifrolumab-fnia) prescribing information 2021.
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