Iberdomide Demonstrates Significant Improvement in Active SLE Treatment

Iberdomide demonstrated significant improvement in the treatment of patients with active systemic lupus erythematosus (SLE), according to study results published in Annals of the Rheumatic Diseases.

In this phase 2, multinational, randomized, placebo-controlled, double-blind study, patients aged at least 18 years with a diagnosis of SLE for at least 6 months, an SLE Disease Activity Index 2000 score of at least 6 points, and who tested positive for autoantibodies associated with SLE (N=288) were randomized (2:2:1:2) to receive either oral iberdomide (0.45 mg, 0.3 mg, or 0.15 mg) or placebo once daily for 24 weeks while continuing their standard-of-care medications.

To conduct pharmacokinetic analysis, predose blood samples were collected at baseline, week 4, week 12, and week 24. These samples were analyzed for whole blood leucocytes, plasma proteins, and whole blood gene expression. Analyzed cells included B cells (CD19+ and CD20+), T cells (including CD4+ and CD8+), plasmablasts, plasmacytoid dendritic cells, and myeloid dendritic cells, as well as T helper 17 cells, regulatory T cells, and T follicular helper cells.

The DxTerity Autoimmune Profiler (DxTerity, Rancho Dominguez, California) was used to analyze whole blood for subsequent gene expression. Using chemical ligation probe amplification technology for generating polymerase chain reaction products, the samples were then separated by capillary electrophoresis for the following gene modules:

• B cell (CD19, BACH2, and CD22);
• Type I IFN (IFI27, IFI44, IFI44L, and RSAD218);
• Ikaros (eQTL) type I IFN (HERC5, IFI6, IFIT1, MX1, and TNFRSF219); and
• T cell exhaustion (CTLA4, IL7R, LAG3, PDCD1, and ABCE119).

Linear pharmacokinetics were exhibited by iberdomide. Exposure increased in a dose-related manner over the dose range of 0.15 mg to 0.45 mg once daily, with a 3-fold dose increase resulting in an approximately 2.5-fold increase in the area under the concentration-time curve at steady state. The researchers used pharmacodynamic analyses to show that iberdomide treatment reduced activity of the B cell and type I IFN pathways. This was evident in reductions in total B cells and B cells expressing the gene for the B lymphocyte stimulator (BLyS) receptor and in switched memory B cells. They indicated that elevated BLyS levels, as documented in patients with SLE and shown to correlate with disease activity, induced plasmablast differentiation and drove autoantibody production in SLE.

Potential limitations of this study include the length of treatment; moreover, participants’ concomitant medication use (antimalarials and immunosuppressants) and ancestral diversity may impact these findings. According to the researchers, results of exploratory cut point analyses require validation in future studies.

The study authors concluded, “[I]berdomide showed significant improvement in the treatment of patients with active SLE.” They continued, “This study confirmed the mechanism of action of iberdomide in vivo in patients with SLE and identified the high type I IFN gene signature as a predictive biomarker for evaluation as a selection tool in future clinical studies of iberdomide.”

Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Lipsky PE, Vollenhoven RV, Dörner T, et al. Biological impact of iberdomide in patients with active systemic lupus erythematosus. Ann Rheum Dis. Published online April 27, 2022. doi:10.1136/annrheumdis-2022-222212