SAT0225 Cereblon modulator CC-220 decreases naÏve and memory B cells and plasmacytoid dendritic cells in systemic lupus erythematosus (SLE) patients: exposure-response results from a phase 2A proof of concept study. (15th June 2017)

• Record Type: Journal Article
• Authors: Gaudy, A; Ye, Y; Korish, S; Hough, D; Weiswasser, M; Choi, S; Furie, R; Werth, V; Schafer, P
• Is Part Of: Annals of the rheumatic diseases. Volume 76(2017)Supplement 2
• Page Start: 858
• Page End: 859
• Publication Date: 2017-06-15
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2017-eular.3036
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: CC-220 is a cereblon E3 ligase modulatory compound currently in development for the treatment of Systemic Lupus Erythematosus as well as other autoimmune conditions and multiple myeloma. As a high affinity ligand for cereblon, CC-220 administration results in significant reductions in ikaros (IKZF1) and aiolos (IKZF3), transcription factors which are genetically linked to SLE risk, and are overexpressed in the peripheral blood of SLE patients compared to healthy controls. Objectives: To describe the pharmacokinetics (PK), pharmacodynamics (PD), and the PK-PD relationship of CC-220 in subjects with SLE. Methods: CC-220-SLE-001 is a randomized, double-blinded, placebo-controlled, phase 2a dose escalation study to investigate the safety, PK, PD, and efficacy of CC-220 in patients with SLE. Forty-two (42) adult SLE subjects fulfilling SLE ACR criteria, having a history of SLE for ≥6 months and a baseline Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) score ≥4 were randomized to placebo or 1 of 4 escalating doses of CC-220 (0.3 mg QOD, 0.3 mg QD, 0.6/0.3 mg alternating QD, or 0.6 mg QD). Results: CC-220 concentration-time profiles demonstrated dose proportionality between cohorts, with moderate accumulation in the non-alternating dose cohort. CC-220 significantly reduced total CD20+ B cells by as much as 96%, immature B cells by as much as 91.2%, switched memory B cells by as much as 81.4%, BAFFR+ B cells by as much as 67.5%, and plasmacytoid dendritic cells (pDCs) by as much as 86.5% (Day 85 median percent change from baseline). Whereas reductions in B cells were observed, CD4+ as well as CD8+ T cells increased, and the rise in T cells paralleled the observed increase in plasma cells in those subjects who received the highest dose (0.6 mg). An exposure-response analysis demonstrated decreasing B cells, pDCs and neutrophils with increased exposure to CC-220. Conclusions: It was determined that 0.3 mg QD to 0.6/0.3 mg alternating QD reduced concentrations of B cells and pDC's while avoiding neutropenia. These findings, in combination with the PK, safety, and exploratory efficacy data, support continued development of CC-220 in SLE. Disclosure of Interest: A. Gaudy Shareholder of: Celgene, Employee of: Celgene, Y. Ye Shareholder of: Celgene, Employee of: Celgene, S. Korish Shareholder of: Celgene, Employee of: Celgene, D. Hough Shareholder of: Celgene, Employee of: Celgene, M. Weiswasser Shareholder of: Celgene, Employee of: Celgene, S. Choi Shareholder of: Celgene, Employee of: Celgene, R. Furie Consultant for: Celgene, V. Werth Grant/research support from: Celgene, Consultant for: Celgene, P. Schafer Shareholder of: Celgene, Employee of: Celgene