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

Abstract

BackgroundCC-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.ObjectivesTo describe the pharmacokinetics (PK), pharmacodynamics (PD), and the PK-PD relationship of CC-220 in subjects with SLE.MethodsCC-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).ResultsCC-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.ConclusionsIt 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 InterestA. 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

Targeted protein degradation: expanding the toolbox

“…Recent observations indicate that IMiDs and PROTACs are poised to have a strong impact on drug discovery in years to come ( Table 1). The clinical efficacy of IMiDs is driven at least in part by their capacity to induce CRBN-mediated degradation of neo-substrates: cancer cells become resistant to the multiple myeloma IMiD drug lenalidomide upon mutation of a single amino acid in IKFZ3 that rescues this transcription factor from proteolytic degradation 7 ; haploinsufficient expression of CK1α sensitizes myelodysplastic syndrome (MDS) cells with deletion of chromosome 5q (del(5q)) to the CRBN-mediated degradation of CK1α by lenalidomide in patients with MDS (5q)15; and treatment with C-220, a CRBN modulator that induces a more potent degradation of IKFZ1 and IKFZ3 than previous IMiDs 16 , elicits positive response in patients with systemic lupus erythematosus in a phase 2a study 17 . Preclinical and clinical studies have demonstrated multiple routes of administration, including oral 18 .…”

Safety and efficacy of biological agents in the treatment of Systemic Lupus Erythematosus (SLE)

“…There were no signi cant outcomes in the disease activity indices, composite responder rates or adverse events in the following group of drugs; anti-dsDNA complexing Abetimus 30 selective JAK 1 and 2 inhibitors Baricitinib 31 , BTK inhibitors Evobrutinib 32 , Fenebrutinib 33 , high a nity cereblon ligand CC-220/Iberdomide 34,35 , tolerogenic peptides Edratide 36 , anti CD22 monoclonal antibody Epratuzumab [37][38][39] , anti IL-6 antibody PF-04326921 4040 Vobarilizumab 41 anti IL-10 monoclonal antibody BT063 42 , P140 peptide Lupuzor 43 and recombinant soluble human FcyRIIb SM101 44…”

Novel Treatments in Lupus

“…CC-220 showed some efficacy but there were important safety issues in a 12-week, phase II, dose-escalation study of 42 patients and 14% of patients stopped treatment because of adverse effects. Higher doses of CC-220 were associated with neutropenia, pneumonia, and dermatitis ( 41 ).…”