Biological impact of iberdomide in patients with active systemic lupus erythematosus

Peter E Lipsky, Ronald van Vollenhoven, Thomas Dörner, Victoria P Werth, Joan T Merrill, Richard Furie, Milan Petronijevic, Benito Velasco Zamora, Maria Majdan, Fedra Irazoque-Palazuelos, Robert Terbrueggen, Nikolay Delev, Michael Weiswasser, Shimon Korish, Mark Stern, Sarah Hersey, Ying Ye, Allison Gaudy, Zhaohui Liu, Robert Gagnon, Shaojun Tang, Peter H Schafer, Peter E Lipsky, Ronald van Vollenhoven, Thomas Dörner, Victoria P Werth, Joan T Merrill, Richard Furie, Milan Petronijevic, Benito Velasco Zamora, Maria Majdan, Fedra Irazoque-Palazuelos, Robert Terbrueggen, Nikolay Delev, Michael Weiswasser, Shimon Korish, Mark Stern, Sarah Hersey, Ying Ye, Allison Gaudy, Zhaohui Liu, Robert Gagnon, Shaojun Tang, Peter H Schafer

Abstract

Objectives: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE).

Methods: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.15 mg (n=42), 0.3 mg (n=82) or 0.45 mg (n=81). Pharmacodynamic changes in whole blood leucocytes were measured by flow cytometry, regulatory T cells (Tregs) by epigenetic assay, plasma cytokines by ultrasensitive cytokine assay and gene expression by Modular Immune Profiling.

Results: Iberdomide exhibited linear pharmacokinetics and dose-dependently modulated leucocytes and cytokines. Compared with placebo at week 24, iberdomide 0.45 mg significantly (p<0.001) reduced B cells, including those expressing CD268 (TNFRSF13C) (-58.3%), and plasmacytoid dendritic cells (-73.9%), and increased Tregs (+104.9%) and interleukin 2 (IL-2) (+144.1%). Clinical efficacy was previously reported in patients with high IKZF3 expression and high type I interferon (IFN) signature at baseline and confirmed here in those with an especially high IFN signature. Iberdomide decreased the type I IFN gene signature only in patients with high expression at baseline (-81.5%; p<0.001) but decreased other gene signatures in all patients.

Conclusion: Iberdomide significantly reduced activity of type I IFN and B cell pathways, and increased IL-2 and Tregs, suggesting a selective rebalancing of immune abnormalities in SLE. Clinical efficacy corresponded to reduction of the type I IFN gene signature.

Trial registration number: NCT03161483.

Keywords: B-Lymphocytes; immune system diseases; lupus Erythematosus, Systemic.

Conflict of interest statement

Competing interests: PEL: RILITE Foundation—grant support. RvV: Bristol Myers Squibb, GlaxoSmithKline and Eli Lilly—research support; UCB—research support, consultancy and speaker; Pfizer—support for educational programmes, consultancy and speaker; Roche—support for educational programmes; AbbVie, Galapagos and Janssen—consultancy and speaker; AstraZeneca, Biogen, Biotest, Celgene, Gilead and Servier—consultancy. TD: Charite Universitätsmedizin Berlin and DRFZ Berlin, Germany; AbbVie, Bristol Myers Squibb, Bristol Myers Squibb/Celgene, Eli Lilly, EMD Serono, Janssen, Novartis, Roche and Samsung—support for clinical studies and honoraria for scientific advice. VPW: Celgene, MedImmune, Resolve, Genentech, Idera, Janssen, Lilly, Biogen, Bristol Myers Squibb, Gilead, Amgen, Medscape, Nektar, Incyte, EMD Serono, CSL Behring, Principia, Crisalis, Viela Bio, Argenx, Kirin, AstraZeneca, AbbVie, GlaxoSmithKline, AstraZeneca, Cugene, UCB, Corcept and Beacon Bioscience—consultancy; and Celgene, Janssen, Biogen, Gilead, AstraZeneca, Viela, Amgen and Lupus Research Alliance/Bristol Myers Squibb—research support. JTM: UCB, GlaxoSmithKline, AbbVie, EMD Serono, RemeGen, Celgene/Bristol Myers Squibb, AstraZeneca, Lilly, Daiichi Sankyo, Servier, ImmuPharma, Amgen, Janssen, Lilly, Genentech, Resolve, Alpine, Aurinia, Astellas, Alexion and Provention—consultancy; and GlaxoSmithKline and AstraZeneca—conducts research. RAF: Bristol Myers Squibb—research/grant support and consultancy. MP and JVZ: Bristol Myers Squibb, Janssen, Pfizer, Roche and Takeda—consultancy. MM: Bristol Myers Squibb, Novartis, Lilly, Amgen, UCB and Medac—speaker. FI-P: Bristol Myers Squibb, Janssen, Pfizer, Roche and Takeda—speaker and advisor. RT: DxTerity Diagnostics—stock ownership and officer. ND, MW, SK, MS, YY, AG, ZL, RG and PHS: Bristol Myers Squibb—employment and shareholder. SH: Bristol Myers Squibb—employment; and Bristol Myers Squibb, JNJ and Novartis—shareholder. ST: Bristol Myers Squibb – employment (at the time of the study) and shareholder.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Time course of change from baseline during iberdomide treatment in whole blood leucocyte counts and selected B cells, T cells and NK cells by flow cytometry (Covance, Indianapolis, Indiana, USA) (A), CD268, plasma blasts, switched memory B cells DC subset counts and plasma cells by flow cytometry (B) and Tregs, Tfh cells and Th17 cells by epigenetic assay (Epiontis ID, Epiontis GmbH, Berlin, Germany) (C). *p≤0.05; **p≤0.01; ***p≤0.001 vs placebo. Values shown are the treatment comparison vs placebo of adjusted mean per cent change from baseline. See online supplemental table 2 for numeric data. BLyS, B lymphocyte stimulator; DC, dendritic cell; NK, natural killer; Tfh, T follicular helper; Th17, T helper 17; Tregs, regulatory T cells.
Figure 2
Figure 2
Change from baseline in plasma cytokines during iberdomide treatment by ultrasensitive cytokine assays (Erenna, EMD Millipore, Burlington, Massachusetts, USA). *p≤0.05; **p≤0.01; ***p≤0.001 vs placebo. Values shown are the treatment comparison vs placebo of adjusted mean per cent change from baseline. See online supplemental table 3 for numeric data. BLyS, B lymphocyte stimulator; IL, interleukin.
Figure 3
Figure 3
Change from baseline in whole blood gene expression during iberdomide treatment by multiplex PCR-based chemical ligation probe amplification target capture on the ThermoFisher ABI 3500xL DX Genetic Analyzer (DxTerity CLIA-certified laboratory)a. *p≤0.05; **p≤0.01; ***p≤0.001. aB cell module: CD19, BACH2 and CD22; type I IFN module: IFI27, IFI44, IFI44L and RSAD2; Ikaros type I IFN module: HERC5, IFI6, IFIT1, MX1 and TNFRSF21; and T cell exhaustion module: CTLA4, IL7R, LAG3, PDCD1 and ABCE1. Values shown are the treatment comparison vs placebo of adjusted mean per cent change from baseline. See online supplemental table 4 for numeric data. IFN, interferon.
Figure 4
Figure 4
Patient subsets based on peripheral blood gene expression at baseline. The cut-offs were set a priori based on an independent training data set (96 samples from patients with SLE, data not shown). The type I IFN module and the Ikaros type I IFN (eQTL) module had bimodal distributions and the cut-offs were set at the antimode: type I IFN module (IFI27, IFI44, IFI44L and RSAD2)=−1.38; Ikaros type I IFN module (HERC5, IFI6, IFIT1, MX1 and TNFRSF21)=−0.76. The distributions of Ikaros, Aiolos and B cell module were unimodal, and the cut-offs were set at the median: Ikaros (IKZF1)=−0.58; Aiolos (IKZF3)=−0.49; B cell module (CD19, BACH2 and CD22)=−0.3; T cell exhaustion module (CTLA4, IL7R, LAG3, PDCD1 and ABCE1)=−0.51. eQTL, expression quantitative trait locus; IFN, interferon.
Figure 5
Figure 5
Clinical efficacy treatment comparison (week 24 SRI-4 response rate, iberdomide 0.45 mg—placebo) within prespecified patient subsets defined by gene expression at baseline. Gene module score cut-offs were set as described in figure 5. See online supplemental table 5 for numeric data. IFN, interferon; SLE, systemic lupus erythematosus; SRI-4, SLE Responder Index-4.
Figure 6
Figure 6
SRI-4 response rate at week 24 in the patient subsets defined by type I IFN gene signature at baseline. Δ=stratified difference from placebo (95% CI); n=number of responders; N=number of patients per subset within each treatment group. IFN, interferon; SLE, systemic lupus erythematosus; SRI-4, SLE Responder Index-4.
Figure 7
Figure 7
Relationship between baseline type I IFN signature and SRI-4 response rates at week 24 comparing placebo and iberdomide 0.45 mg treated SRI-4 cumulative response rates across the range of baseline type I IFN signature values (IFI27, IFI44, IFI44L and RSAD2). In exploratory analysis using bootstrapping and aggregating of thresholds from trees, the type I IFN signature optimal cut point was at 0.615 (interaction p=0.0037), SRI-4 at 0.45 mg=74% vs placebo=20%, OR=11.3 (2.9–43.8). this ‘IFN-Superhigh’ cut point captured 90/288 (31%) patients. At the extreme IFN >1.31 (top 14% of patients), in the iberdomide 0.45 mg group, 11/11 (100%) patients had an SRI-4 response. IFN, interferon; SLE, systemic lupus erythematosus; SRI-4, SLE Responder Index-4.

References

    1. Kaul A, Gordon C, Crow MK, et al. . Systemic lupus erythematosus. Nat Rev Dis Primers 2016;2:16039. 10.1038/nrdp.2016.39
    1. Wang Y-F, Zhang Y, Lin Z, et al. . Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups. Nat Commun 2021;12:772. 10.1038/s41467-021-21049-y
    1. John LB, Ward AC. The Ikaros gene family: transcriptional regulators of hematopoiesis and immunity. Mol Immunol 2011;48:1272–8. 10.1016/j.molimm.2011.03.006
    1. Nakayama Y, Kosek J, Capone L, et al. . Aiolos overexpression in systemic lupus erythematosus B cell subtypes and BAFF-induced memory B cell differentiation are reduced by CC-220 modulation of cereblon activity. J Immunol 2017;199:2388–407. 10.4049/jimmunol.1601725
    1. Schafer PH, Ye Y, Wu L, et al. . Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus. Ann Rheum Dis 2018;77:1516–23. 10.1136/annrheumdis-2017-212916
    1. Bandyopadhyay S, Duré M, Paroder M, et al. . Interleukin 2 gene transcription is regulated by Ikaros-induced changes in histone acetylation in anergic T cells. Blood 2007;109:2878–86. 10.1182/blood-2006-07-037754
    1. Lessard CJ, Adrianto I, Ice JA, et al. . Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility loci for systemic lupus erythematosus in a large-scale multiracial replication study. Am J Hum Genet 2012;90:648–60. 10.1016/j.ajhg.2012.02.023
    1. Wang C, Ahlford A, Järvinen TM, et al. . Genes identified in Asian SLE GWASs are also associated with SLE in Caucasian populations. Eur J Hum Genet 2013;21:994–9. 10.1038/ejhg.2012.277
    1. Westra H-J, Peters MJ, Esko T, et al. . Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 2013;45:1238–43. 10.1038/ng.2756
    1. Vyse TJ, Cunninghame Graham DS. Trans-ancestral fine-mapping and epigenetic annotation as tools to delineate functionally relevant risk alleles at IKZF1 and IKZF3 in systemic lupus erythematosus. Int J Mol Sci 2020;21. 10.3390/ijms21218383. [Epub ahead of print: 09 Nov 2020].
    1. Matyskiela ME, Zhang W, Man H-W, et al. . A cereblon modulator (CC-220) with improved degradation of Ikaros and Aiolos. J Med Chem 2018;61:535–42. 10.1021/acs.jmedchem.6b01921
    1. Furie R, Werth VP, Gaudy A. A randomized, placebo-controlled, double-blind ascending-dose, safety, efficacy, pharmacokinetics and pharmacodynamics study of CC-220 in subjects with systemic lupus erythematosus [presentation]. Annual Meeting of the American College of Rheumatology, San Diego, CA, 2017.
    1. Merrill JT, Werth VP, Furie R, et al. . Phase 2 trial of iberdomide in systemic lupus erythematosus. N Engl J Med 2022;386:1034–45. 10.1056/NEJMoa2106535
    1. Ye Y, Gaudy A, Schafer P, et al. . First-in-human, single- and multiple-ascending-dose studies in healthy subjects to assess pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide, a novel cereblon E3 ligase modulator. Clin Pharmacol Drug Dev 2021;10:471–85. 10.1002/cpdd.869
    1. Baron U, Werner J, Schildknecht K, et al. . Epigenetic immune cell counting in human blood samples for immunodiagnostics. Sci Transl Med 2018;10. 10.1126/scitranslmed.aan3508. [Epub ahead of print: 01 08 2018].
    1. Burska AN, Thu A, Parmar R, et al. . Quantifying circulating Th17 cells by qPCR: potential as diagnostic biomarker for rheumatoid arthritis. Rheumatology 2019;58:2015–24. 10.1093/rheumatology/kez162
    1. van Roon JAG, Moret FM, Blokland SLM. Epigenetic cell counting: a novel tool to quantify immune cells in salivary glands detects robust correlations of T follicular helper cells with immunopathology [abstract]. Arthritis Rheumatol 2017;69:2830.
    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
    1. McKinney EF, Lee JC, Jayne DRW, et al. . T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection. Nature 2015;523:612–6. 10.1038/nature14468
    1. Huang X, Sun Y, Trow P, et al. . Patient subgroup identification for clinical drug development. Stat Med 2017;36:1414–28. 10.1002/sim.7236
    1. Morimoto S, Nakano S, Watanabe T, et al. . Expression of B-cell activating factor of the tumour necrosis factor family (BAFF) in T cells in active systemic lupus erythematosus: the role of BAFF in T cell-dependent B cell pathogenic autoantibody production. Rheumatology 2007;46:1083–6. 10.1093/rheumatology/kem097
    1. Geginat J, Vasco M, Gerosa M, et al. . IL-10 producing regulatory and helper T-cells in systemic lupus erythematosus. Semin Immunol 2019;44:101330. 10.1016/j.smim.2019.101330
    1. Thomas RM, Chunder N, Chen C, et al. . Ikaros enforces the costimulatory requirement for IL2 gene expression and is required for anergy induction in CD4+ T lymphocytes. J Immunol 2007;179:7305–15. 10.4049/jimmunol.179.11.7305
    1. Bell CJM, Sun Y, Nowak UM, et al. . Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells. J Autoimmun 2015;56:66–80. 10.1016/j.jaut.2014.10.002
    1. Perotti EA, Georgopoulos K, Yoshida T. An Ikaros promoter element with dual epigenetic and transcriptional activities. PLoS One 2015;10:e0131568. 10.1371/journal.pone.0131568
    1. Brohawn PZ, Streicher K, Higgs BW, et al. . Type I interferon gene signature test-low and -high patients with systemic lupus erythematosus have distinct gene expression signatures. Lupus 2019;28:1524–33. 10.1177/0961203319885447
    1. Hoffman RW, Merrill JT, Alarcón-Riquelme MME, et al. . Gene expression and pharmacodynamic changes in 1,760 systemic lupus erythematosus patients from two phase III trials of BAFF blockade with tabalumab. Arthritis Rheumatol 2017;69:643–54. 10.1002/art.39950
    1. Catalina MD, Bachali P, Yeo AE, et al. . Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus. JCI Insight 2020;5:e140380. 10.1172/jci.insight.140380
    1. Kirou KA, Lee C, George S, et al. . Activation of the interferon-alpha pathway identifies a subgroup of systemic lupus erythematosus patients with distinct serologic features and active disease. Arthritis Rheum 2005;52:1491–503. 10.1002/art.21031
    1. Kirou KA, Mavragani CP, Crow MK. Activation of type I interferon in systemic lupus erythematosus. Expert Rev Clin Immunol 2007;3:579–88. 10.1586/1744666X.3.4.579
    1. 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
    1. Arriens C, Raja Q, Husain SA. Increased risk of progression to lupus nephritis for lupus patients with elevated interferon signature [abstract]. Arthritis Rheumatol 2019;71:1914.

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