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Systemic lupus erythematosus
Biological impact of iberdomide in patients with active systemic lupus erythematosus
  1. Peter E Lipsky1,
  2. Ronald van Vollenhoven2,
  3. Thomas Dörner3,
  4. Victoria P Werth4,
  5. Joan T Merrill5,
  6. Richard Furie6,
  7. Milan Petronijevic7,
  8. Benito Velasco Zamora8,
  9. Maria Majdan9,
  10. Fedra Irazoque-Palazuelos10,
  11. Robert Terbrueggen11,
  12. Nikolay Delev12,
  13. Michael Weiswasser12,
  14. Shimon Korish12,
  15. Mark Stern12,
  16. Sarah Hersey12,
  17. Ying Ye12,
  18. Allison Gaudy12,
  19. Zhaohui Liu12,
  20. Robert Gagnon12,
  21. Shaojun Tang12,
  22. Peter H Schafer12
  1. 1 RILITE Foundation and AMPEL BioSolutions, Charlottesville, Virginia, USA
  2. 2 Amsterdam University Medical Centers, Amsterdam, The Netherlands
  3. 3 German Rheumatism Research Center, Charité University Hospital, Berlin, Germany
  4. 4 University of Pennsylvania and the Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania, USA
  5. 5 Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  6. 6 Department of Rheumatology, Northwell Health, Great Neck, New York, USA
  7. 7 Military Medical Academy, Belgrade, Serbia
  8. 8 Instituto CER S.A, Buenos Aires, Argentina
  9. 9 Samodzielny Publiczny Szpital Kliniczny Nr 4 w Lublinie, Medical University of Lublin, Lublin, Poland
  10. 10 Centro de Investigación y Tratamiento Reumatológico SC, Mexico City, Mexico
  11. 11 DxTerity Diagnostics, Rancho Dominguez, California, USA
  12. 12 Bristol Myers Squibb, Princeton, New Jersey, USA
  1. Correspondence to Dr Peter E Lipsky, RILITE Foundation, Charlottesville, USA; peterlipsky{at}comcast.net

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.

  • lupus Erythematosus, Systemic
  • B-Lymphocytes
  • immune system diseases

Data availability statement

The Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html

https://creativecommons.org/licenses/by/4.0/

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/.

http://dx.doi.org/10.1136/annrheumdis-2022-222212

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    Data availability statement

    The Bristol Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html

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    Footnotes

    • Handling editor Josef S Smolen

    • Contributors Conception or design of the work: PEL, RvV, TD, VPW, JTM, RAF, ND, MW, SK, YY, AG, ZL and PHS. Acquisition, analysis or interpretation of data and drafted or substantially revised the work: all authors. Author acting as guarantor: PHS.

    • Funding This study was sponsored by Bristol Myers Squibb.

    • 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.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.