Iberdomide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled, ascending-dose, phase 2a study

Abstract

Objective: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of iberdomide in patients with SLE. Iberdomide is a high-affinity cereblon ligand that targets the hematopoietic transcription factors Ikaros and Aiolos for proteasomal degradation.

Methods: A 12-week, multicentre, double-blind, placebo-controlled, dose-escalation study in active SLE was followed by a 2-year, open-label active treatment extension phase (ATEP) (NCT02185040). In the dose-escalation phase, adults with active SLE were randomised to oral placebo or iberdomide (0.3 mg every other day, 0.3 mg once daily, 0.6 mg and 0.3 mg alternating once daily, or 0.6 mg once daily). Primary endpoints were safety and tolerability.

Results: The dose-escalation phase enrolled 42 patients, with 33 completing this phase and 17 patients enrolling into the ATEP. In the dose-escalation phase, the most common treatment-emergent adverse events (TEAEs; iberdomide/placebo groups) were nausea (20.6%/12.5%), diarrhoea (17.6%/12.5%) and upper respiratory tract infection (11.8%/12.5%). Most TEAEs were mild or moderate in severity and more common in the highest dose groups in both study phases. In the dose-escalation phase, Physician's Global Assessment and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity scores improved relative to baseline and placebo in all iberdomide groups, with a trend toward continued score improvements in the ATEP. In the dose-escalation phase, iberdomide treatment resulted in dose-dependent reductions in total B cells and plasmacytoid dendritic cells in blood. Improvements in CLASI activity scores correlated with plasmacytoid dendritic cell depletion.

Conclusions: These proof-of-concept findings suggest a favourable benefit/risk ratio in SLE for iberdomide, a drug with a novel immunomodulatory mechanism of action, supporting further clinical investigation.

Keywords: autoimmune diseases; lupus erythematosus; pharmacokinetics; systemic.

Figure 1

Mean change from baseline in (A) hybrid SELENA-SLEDAI scores, (B) CLASI scores, (C) PGA scores, D) tender joint count (TJC) and (E) swollen joint count (SJC) in the ITT population during the dose escalation part, and (F) mean change from baseline in CLASI score in patients with baseline CLASI ≥10. ALTN, alternating once daily; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; hSS, hybrid SELENA-SLEDAI; ITT, intent to treat; PGA, Physician’s Global Assessment; QD, once daily; QOD, every other day; SELENA-SLEDAI, Safety of Estrogens in Systemic Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index.

Figure 2

Changes in (A) CD20+ B cells, (B) immature B cells, (C) switched memory B cells, (D) BAFFR+ B cells, (E) myeloid dendritic cells, (F) plasmacytoid dendritic cells, (G) CD4+ T cells, (H) CD8+ T cells following dosing with placebo or iberdomide in the part 1 PD population. *Significantly different from placebo using two-sided 95% CIs based on analysis of covariance model with the percentage change from baseline as response variable and the treatment and baseline score as factors. ALTN, alternating once daily; BAFFR+, B-cell-activating factor receptor positive; QD, once daily; QOD, every other day.

Figure 3

Relationships between change in CLASI score and (A) pDCs in blood in all iberdomide-treated patients, (B) pDCs in blood in iberdomide-treated patients with baseline CLASI score ≥10, (C) B cells in blood in all iberdomide-treated patients and (D) B cells in blood in iberdomide-treated patients with baseline CLASI score ≥10. ALTN, alternating QD; CLASI, Cutaneous Lupus Erythematosus Disease Area and Severity Index; pDCs, plasmacytoid dendritic cells; QD, once daily; QOD, every other day.