Biological impact of iberdomide in patients with active systemic lupus erythematosus.

Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros ( 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. 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 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. NCT03161483.

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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.