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
BackgroundCC-220 is an immunomodulatory compound that binds to cereblon (CRBN), part of the CRL4CRBN E3 ubiquitin ligase complex, which has been shown to ubiquitinate the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Polymorphisms at the IKZF1 and IKZF3 loci have been associated with risk of systemic lupus erythematosus (SLE).ObjectivesWe explored CRBN, IKZF1, and IKZF3 gene expression in peripheral blood mononuclear cells (PBMC) from SLE patients; the effect of CC-220 on Ikaros and Aiolos protein levels and SLE autoantibody production in vitro; and the impact of CC-220 on immunological parameters in a double-blinded, placebo-controlled, single-ascending dose, healthy volunteer phase 1 clinical trial.MethodsCRBN, IKZF1, and IKZF3 gene expression were measured by qRT-PCR. Ikaros and Aiolos protein levels were measured by western blot and flow cytometry. Anti-dsDNA and anti-phospholipid autoantibodies were measured from SLE PBMC cultures treated for 7 days with CC-220. In the phase 1 healthy volunteer study, 56 subjects were randomized and enrolled in 7 cohorts, with 6 subjects per cohort receiving a single oral dose of CC-220 (0.03-6 mg) and 2 subjects per cohort receiving placebo. CD19+ B cells, CD3+ T cells, and intracellular Aiolos were measured by flow cytometry. IL-2 and IL-1β production were stimulated with anti-CD3 or LPS, respectively, in the TruCulture ex vivo whole blood assay system.ResultsCompared to normal PBMC, SLE PBMC expressed significantly higher levels of CRBN (1.5-fold), IKZF1 (2.1-fold), and IKZF3 (4.1-fold). CC-220 treatment of whole blood significantly reduced Aiolos and Ikaros protein levels in B cells, T cells, and monocytes, but not in granulocytes. In cultures of SLE PBMC, CC-220 inhibited anti-dsDNA and anti-phospholipid autoantibody production with an IC50 of $≈ $10 nM. Following administration of single doses of CC-220 to healthy volunteers, there was a treatment-related decrease in intracellular Aiolos, with minimum mean percent of baseline values of $≈ $12%>28% in B cells and 0%>33% in T cells, for 0.3-6 mg. There was also a treatment-related decrease in absolute CD19+ B cells and CD3+ T cells, with minimum mean percent of baseline values of $≈ $41%>67% for B cells and 66%>73% for T cells, for 2-6 mg. CC-220 administration also resulted in increased IL-2 (maximum mean percent of baseline values ranging from 247%>1896% for 0.1-6 mg), and a decrease in IL-1β (minimum mean percent of baseline values of $≈ $11% at 6 mg).ConclusionsThese results demonstrate that CRBN, IKZF1, and IKZF3 mRNA are overexpressed in PBMC of SLE patients. Targeting the CRL4CRBN E3 ubiquitin ligase with CC-220 resulted in a potent reduction in Aiolos and Ikaros protein levels in B cells, T cells, and monocytes, and inhibited autoantibody production. Administration of single doses of CC-220 (0.3-6 mg) reduced intracellular Aiolos protein expression in B cells and T cells, reduced absolute B-cell and T-cell counts in peripheral blood, and increased T-cell-derived IL-2 production and decreased LPS-induced...
BackgroundCC-220 is a CUL4CRBN E3 ubiquitin ligase modulator that binds to cereblon and leads to potent and deep reduction of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are overexpressed in the peripheral blood of Systemic Lupus Erythematosus (SLE) subjects. This study evaluated the safety, and tolerability of CC-220 in subjects with SLE. Exploratory efficacy assessments were included.MethodsSubjects with history of SLE ≥6 months and a baseline of hybrid SELENA-SLEDAI (hSS) score ≥4 were randomized to 1 of 4 escalating doses of CC-220 or matching placebo (PBO). The 4 active treatments were CC-220 0.3 mg QOD, 0.3 mg QD, 0.3 mg alternating with 0.6 mg QD, and 0.6 mg QD; subjects were randomized 4:1 active to PBO in each group for 12 weeks of treatment, followed by 12 weeks of observational follow-up and/or long-term extension. Stable doses of corticosteroids (≤10 mg prednisone or equivalent daily), non-steroidal anti-inflammatory drugs, and antimalarials were permitted. Safety assessments included clinical evaluation of adverse events (AEs), laboratory parameters, electrocardiograms, physical examinations, and overall tolerability. Exploratory efficacy assessments included hSS, Cutaneous Lupus Area and Severity Index (CLASI) skin scores, Physician Global Assessment (PGA), swollen joint counts (SJC), and tender joint counts (TJC).ResultsA total of 42 adult subjects were randomized; 39 subjects were female (93%); Mean age was 47.2 years; 64% were White and 31% were Black or African-American. Mean SLE duration was 9.4 years, with a mean baseline hSS score of 6.6, CLASI activity score of 9.8, and PGA score of 1.3. Seventy-nine percent of subjects completed the study; 9 of 42 subjects discontinued, of which 6 subjects discontinued due to an adverse event (AE): 1 in the placebo group and 5 in the 2 highest CC-220 groups combined. No discontinuations were due to lack of efficacy. Four subjects had serious AEs (highest CC-220 doses: n=2 [pneumonia]; PBO: n=2). Three subjects had neutropenia (grade 3: n=2; grade 1: n=1); 2 subjects in the highest CC-220 dose group had dermatitis, and 1 subject in the 0.3 mg QD and 1 in the 0.6 mg QD dose groups had urticaria. Mean reductions in the CLASI activity score at day 85 ranged from 4.3 to 7.8 in the CC-220 treatment groups compared to an increase of 0.4 in the placebo group. More subjects receiving CC-220 had a ≥4-point reduction in hSS score vs PBO by Day 85 (22.2%>50.0% vs 12.5%).ConclusionsCC-220 was generally well tolerated in this SLE population over 12 weeks of treatment, with neutropenia and dermatitis observed at the highest doses studied. Treatment with CC-220 resulted in a trend toward greater improvement in multiple measures of SLE disease activity compared with PBO. These results support further development of CC-220 in SLE patient population.Disclosure of InterestV. Werth Grant/research support from: Celgene Corporation, Consultant for: Celgene Corporation, R. Furie Consultant for: Celgene Corporation, S. Korish Shareholder of: Celgene Corporatio...
BackgroundSystemic Lupus Erythematosis (SLE) is an autoimmune disease characterized by alterations in B-cells, autoantibody production, and elevations in circulating B-cell activating factor (BAFF). Aiolos single nucleotide polymorphisms and elevations in Aiolos mRNA are associated with SLE susceptibility. CC-220 is a Cullin Ring Ligase 4 Cereblon (CRL4CRBN) E3 Ubiquitin Ligase Modulator that induces ubiquitination and degradation of Aiolos and Ikaros transcription factors. We investigated the effects of CC-220 in B-cells from SLE patients to assess its impact on Aiolos protein levels and B-cell proliferation, differentiation, and antibody production.ObjectivesDetermine the protein levels of the B-cell transcription factors Aiolos and Ikaros in B-cell subtypes of SLE patients and assess the impact of the cereblon modulator CC-220 on Aiolos and Ikaros protein degradation, proliferation, and plasmablast differentiation.MethodsPeripheral blood mononuclear cells (PBMC) were measured for levels of circulating B-cell subtypes, B-cell activation state, and Aiolos and Ikaros protein levels by flow cytometry. Cell types were defined as: CD27-IgD+ naive, CD27+IgD- switched memory, CD27+IgD+ nonswitched memory, and CD27-IgD- double negative B-cells and CD20-CD38+ plasmablasts. Measurements of BAFF, IL-2 and IL-21 from plasma and IgG and IgM were done by ELISA. Plasmablast differentiation was induced by BAFF, IL-2, and IL-21 co-stimulation of B-cell cultures for 5 days in the absence and presence of CC-220.ResultsPlasma samples from SLE patients were found to have higher circulating BAFF, similar IL-2 levels, and reduced IL-21 levels relative to healthy individuals. Alterations in circulating B-cell subtypes occur in SLE patients including reduction of memory and elevations of naive and double negative B-cells. Alterations in biomarkers associated with chronic B-cell activation, including elevation of CD95 and reduction of CD21 and CD23 were also observed. Assessment of the B-cell differentiation transcription factors Aiolos and Ikaros in SLE B-cells showed that Aiolos, but not Ikaros is elevated in naive, switched memory, nonswitched memory, and double negative B-cells. CC-220 treatment reduced Aiolos and Ikaros protein levels in both SLE and healthy individuals in all four B-cell subtypes measured. CC-220 treatment was associated with reduced B-cell proliferation, plasmablast differentiation, and secretion of IgG and IgM in cells co-stimulated with BAFF, IL-2 and IL-21. Similarly, CC-220 reduced the expression of genes involved in B-cell differentiation including IRF-4, Xbp-1, Blimp-1, and IgJ indicating an early blockade in B-cell differntiation.ConclusionsOur observations that SLE is associated with alterations of circulating B-cell subtypes and their activation state, Aiolos overexpression in B-cells, and increases in circulating BAFF support the hypothesis that B-cells play a significant role in SLE pathology. Moreover, these observed changes suggest that B-cells may be predisposed towards plasmablast differentiation an...
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