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      Biological impact of iberdomide in patients with active systemic lupus erythematosus

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          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.

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          Most cited references35

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          Systemic lupus erythematosus

          Arvind Kaul, Caroline Gordon, Mary Crow … (2016)
          Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs, including the skin, joints, the central nervous system and the kidneys. Women of childbearing age and certain racial groups are typically predisposed to developing the condition. Rare, inherited, single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly UV light exposure, Epstein-Barr virus infection and hormonal factors, might initiate the disease, resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been approved for use in SLE in the past 60 years. The 10-year mortality has improved and toxic adverse effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in the future.
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            Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus

            Richard Furie, Munther A. Khamashta, Joan Merrill … (2017)
            Objective To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with moderate‐to‐severe systemic lupus erythematosus (SLE). Methods Patients (n = 305) were randomized to receive intravenous anifrolumab (300 mg or 1,000 mg) or placebo, in addition to standard therapy, every 4 weeks for 48 weeks. Randomization was stratified by SLE Disease Activity Index 2000 score (<10 or ≥10), oral corticosteroid dosage (<10 or ≥10 mg/day), and type I IFN gene signature test status (high or low) based on a 4‐gene expression assay. The primary end point was the percentage of patients achieving an SLE Responder Index (SRI[4]) response at week 24 with sustained reduction of oral corticosteroids (<10 mg/day and less than or equal to the dose at week 1 from week 12 through 24). Other end points (including SRI[4], British Isles Lupus Assessment Group [BILAG]–based Composite Lupus Assessment [BICLA], modified SRI[6], and major clinical response) were assessed at week 52. The primary end point was analyzed in the modified intent‐to‐treat (ITT) population and type I IFN–high subpopulation. The study result was considered positive if the primary end point was met in either of the 2 study populations. The Type I error rate was controlled at 0.10 (2‐sided), within each of the 2 study populations for the primary end point analysis. Results The primary end point was met by more patients treated with anifrolumab (34.3% of 99 for 300 mg and 28.8% of 104 for 1,000 mg) than placebo (17.6% of 102) (P = 0.014 for 300 mg and P = 0.063 for 1,000 mg, versus placebo), with greater effect size in patients with a high IFN signature at baseline (13.2% in placebo‐treated patients versus 36.0% [P = 0.004] and 28.2% [P = 0.029]) in patients treated with anifrolumab 300 mg and 1,000 mg, respectively. At week 52, patients treated with anifrolumab achieved greater responses in SRI(4) (40.2% versus 62.6% [P < 0.001] and 53.8% [P = 0.043] with placebo, anifrolumab 300 mg, and anifrolumab 1,000 mg, respectively), BICLA (25.7% versus 53.5% [P < 0.001] and 41.2% [P = 0.018], respectively), modified SRI(6) (28.4% versus 49.5% [P = 0.002] and 44.7% [P = 0.015], respectively), major clinical response (BILAG 2004 C or better in all organ domains from week 24 through week 52) (6.9% versus 19.2% [P = 0.012] and 17.3% [P = 0.025], respectively), and several other global and organ‐specific end points. Herpes zoster was more frequent in the anifrolumab‐treated patients (2.0% with placebo treatment versus 5.1% and 9.5% with anifrolumab 300 mg and 1,000 mg, respectively), as were cases reported as influenza (2.0% versus 6.1% and 7.6%, respectively), in the anifrolumab treatment groups. Incidence of serious adverse events was similar between groups (18.8% versus 16.2% and 17.1%, respectively). Conclusion Anifrolumab substantially reduced disease activity compared with placebo across multiple clinical end points in the patients with moderate‐to‐severe SLE.
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              Systematic identification of trans eQTLs as putative drivers of known disease associations

              Harm-Jan Westra, Marjolein J Peters, Tõnu Esko … (2013)
              Identifying the downstream effects of disease-associated SNPs is challenging. To help overcome this problem, we performed expression quantitative trait locus (eQTL) meta-analysis in non-transformed peripheral blood samples from 5,311 individuals with replication in 2,775 individuals. We identified and replicated trans eQTLs for 233 SNPs (reflecting 103 independent loci) that were previously associated with complex traits at genome-wide significance. Some of these SNPs affect multiple genes in trans that are known to be altered in individuals with disease: rs4917014, previously associated with systemic lupus erythematosus (SLE), altered gene expression of C1QB and five type I interferon response genes, both hallmarks of SLE. DeepSAGE RNA sequencing showed that rs4917014 strongly alters the 3' UTR levels of IKZF1 in cis, and chromatin immunoprecipitation and sequencing analysis of the trans-regulated genes implicated IKZF1 as the causal gene. Variants associated with cholesterol metabolism and type 1 diabetes showed similar phenomena, indicating that large-scale eQTL mapping provides insight into the downstream effects of many trait-associated variants.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ann Rheum Dis
                Journal ID (iso-abbrev): Ann Rheum Dis
                Journal ID (hwp): annrheumdis
                Journal ID (publisher-id): ard
                Title: Annals of the Rheumatic Diseases
                Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                ISSN (Print): 0003-4967
                ISSN (Electronic): 1468-2060
                Publication date (Print): August 2022
                Publication date (Electronic): 27 April 2022
                Volume: 81
                Issue: 8
                Pages: 1136-1142
                Affiliations
                [1 ] RILITE Foundation and AMPEL BioSolutions , Charlottesville, Virginia, USA
                [2 ] Amsterdam University Medical Centers , Amsterdam, The Netherlands
                [3 ] departmentGerman Rheumatism Research Center , Charité University Hospital , Berlin, Germany
                [4 ] University of Pennsylvania and the Michael J. Crescenz VA Medical Center , Philadelphia, Pennsylvania, USA
                [5 ] Oklahoma Medical Research Foundation , Oklahoma City, Oklahoma, USA
                [6 ] departmentDepartment of Rheumatology , Northwell Health , Great Neck, New York, USA
                [7 ] Military Medical Academy , Belgrade, Serbia
                [8 ] Instituto CER S.A , Buenos Aires, Argentina
                [9 ] Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie, Medical University of Lublin , Lublin, Poland
                [10 ] Centro de Investigación y Tratamiento Reumatológico SC , Mexico City, Mexico
                [11 ] DxTerity Diagnostics , Rancho Dominguez, California, USA
                [12 ] Bristol Myers Squibb , Princeton, New Jersey, USA
                Author notes
                [Correspondence to ] Dr Peter E Lipsky, RILITE Foundation, Charlottesville, USA; peterlipsky@ 123456comcast.net
                Author information
                http://orcid.org/0000-0002-9287-1676
                http://orcid.org/0000-0002-6478-7725
                http://orcid.org/0000-0001-6712-1585
                Article
                Publisher ID: annrheumdis-2022-222212
                DOI: 10.1136/annrheumdis-2022-222212
                PMC ID: 9279852
                PubMed ID: 35477518
                SO-VID: c4a31078-eaa1-428c-9fbb-2d482b6f6ea3
                Copyright © © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
                License:

                This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:  https://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 21 January 2022
                Date accepted : 10 April 2022
                Funding
                Funded by: Bristol Myers Squibb;
                Categories
                Subject: Systemic Lupus Erythematosus
                Subject: 1506
                Subject: 2311
                Subject: 2494
                Custom metadata
                special-feature unlocked

                ScienceOpen disciplines: Immunology
                Keywords: lupus erythematosus, systemic,b-lymphocytes,immune system diseases
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: lupus erythematosus, systemic, b-lymphocytes, immune system diseases

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