Peter Lipsky, MD: Pharmacodynamic effects of iberdomide in active SLE

Peter Lipsky, MD
Peter Lipsky, MD

Poster presenter: Peter Lipsky, MD, RILITE Foundation

Poster title: Iberdomide Decreases B Cells and Plasmacytoid Dendritic Cells, Increases Regulatory T Cells and IL-2, and Has Enhanced Clinical Efficacy in Active Systemic Lupus Erythematosus Patients with High Aiolos or the IFN Gene Expression Signature

Scheduled poster session day and time: Saturday, Nov. 7, 9 – 11 a.m. EST

Visit the Poster Hall

What is your poster about?

Iberdomide is a small molecule, high-affinity ligand of cereblon that has immunomodulatory properties and is currently in development for the treatment of systemic lupus erythematosus (SLE) and multiple myeloma. By binding to cereblon, iberdomide promotes the ubiquitination and proteasomal degradation of 2 zinc finger transcription factors, Ikaros and Aiolos, which are involved in immune cell development and homeostasis. In vitro studies have shown that iberdomide inhibits B-cell differentiation, reducing autoantibodies and production of anti-double-stranded DNA and antiphospholipid antibodies. Iberdomide has also been shown to increase IL-2 production, which is under expressed in the serum of patients with lupus, and increase regulatory T cells.

A randomized, double-blind, placebo-controlled phase 2b dose finding study of iberdomide in patients with active moderate to severe SLE is ongoing. As part of this study, the pharmacodynamic effects of iberdomide on immune cell subsets and cytokine were evaluated.  This poster presents the pharmacodynamic data from the 24-week, placebo-controlled period of the study for patients receiving one of three doses of iberdomide (0.15 mg, 0.3 mg, or 0.45 mg) or placebo.

Why did you decide to investigate this topic?

SLE has an unknown etiology, affects women more frequently than men, and typically begins in the third and fourth decades of life. Manifestations of lupus are widespread, and the chronic nature of the disease is associated with substantial disability. Disease susceptibility is influenced by genes related to immune response and interactions with the hormonal environment. Current pharmacologic treatments for lupus include nonsteroidal anti-inflammatory drugs, corticosteroids, and immunosuppressants. There is a need for effective and safe targeted therapy for patients with SLE.

Two cereblon substrates, Ikaros and Aiolos, have been implicated in the genetic predisposition for SLE and are overexpressed in the peripheral blood of patients with lupus. The effect of iberdomide on these transcription factors supports its use in SLE patients. In vitro studies and a phase 1 trial also supported the immunomodulatory effects of iberdomide in patients with lupus. The pharmacodynamics of iberdomide from this larger phase 2 trial in patients with active lupus provide additional information on the effects of the drug.

What excites you most about your work?

The results of this phase 2 trial, combined with earlier in vitro studies and a phase 1 study, indicate several pharmacologic effects of iberdomide, including reduction of B cells, augmentation of IL-2 production by T cells, and reduced gene expression associated with type 1 interferons and B cells. These effects combined with the clinical activity (as reported in Abstract 901257) suggest that iberdomide may be an effective treatment of active SLE, particularly for those patients with high expression of Aiolos or Type 1 interferon. These data provide support for further study of iberdomide in patients with SLE.

What are you working on next related to this poster? 

Analysis of the pharmacodynamic data showed that iberdomide treatment reduced activity of the B-cell/plasma cell and Type 1 interferon pathways, with reductions in total B cells, B cells expressing tumor necrosis factor receptor super family member 13 C, which is the gene for the BAFF/BLyS receptor, anti-double-stranded DNA antibodies, and Type 1 interferon-inducible genes. Iberdomide increased regulatory T cells and levels of IL-2 and IL-10 cytokines, suggesting a broad rebalance of immune regulation.

Clinical efficacy in patients with active SLE in this phase 2 trial was greater among subgroups who had high expression of Aiolos or the Type 1 interferon gene signature at baseline. This finding may provide an opportunity for precision medicine. Potential biomarkers associated with response to iberdomide will be evaluated in future clinical studies.