Biological impact of iberdomide in patients with active systemic lupus erythematosus
Por:
Lipsky P.E., Vollenhoven R.V., Dörner T., Werth V.P., Merrill J.T., Furie R., Petronijevic M., Velasco Zamora B., Majdan M., Irazoque-Palazuelos F., Terbrueggen R., Delev N., Weiswasser M., Korish S., Stern M., Hersey S., Ye Y., Gaudy A., Liu Z., Gagnon R., Tang S., Schafer P.H.
Publicada:
1 ene 2022
Resumen:
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. © 2022 BMJ Publishing Group. All rights reserved.
Filiaciones:
Lipsky P.E.:
RILITE Foundation and AMPEL BioSolutions, Charlottesville, VA, United States
Vollenhoven R.V.:
Amsterdam University Medical Centers, Amsterdam, Netherlands
Dörner T.:
German Rheumatism Research Center, Charité University Hospital, Berlin, Germany
Werth V.P.:
University of Pennsylvania and the Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States
Merrill J.T.:
Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
Furie R.:
Department of Rheumatology, Northwell Health, Great Neck, NY, United States
Petronijevic M.:
Military Medical Academy, Belgrade, Serbia
Velasco Zamora B.:
Instituto CER S.A, Buenos Aires, Argentina
Majdan M.:
Samodzielny Publiczny Szpital Kliniczny Nr 4 W Lublinie, Medical University of Lublin, Lublin, Poland
Irazoque-Palazuelos F.:
Centro de Investigación y Tratamiento Reumatológico SC, Mexico City, Mexico
Terbrueggen R.:
DxTerity Diagnostics, Rancho DominguezCA, United States
Delev N.:
Bristol Myers Squibb, Princeton, NJ, United States
Weiswasser M.:
Bristol Myers Squibb, Princeton, NJ, United States
Korish S.:
Bristol Myers Squibb, Princeton, NJ, United States
Stern M.:
Bristol Myers Squibb, Princeton, NJ, United States
Hersey S.:
Bristol Myers Squibb, Princeton, NJ, United States
Ye Y.:
Bristol Myers Squibb, Princeton, NJ, United States
Gaudy A.:
Bristol Myers Squibb, Princeton, NJ, United States
Liu Z.:
Bristol Myers Squibb, Princeton, NJ, United States
Gagnon R.:
Bristol Myers Squibb, Princeton, NJ, United States
Tang S.:
Bristol Myers Squibb, Princeton, NJ, United States
Schafer P.H.:
Bristol Myers Squibb, Princeton, NJ, United States
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