PORTLAND – The investigational agent CC-220 showed some efficacy but important safety signals in a 12-week, phase II, dose-escalation study of 42 patients with systemic lupus erythematosus (SLE).
In all, 14% of patients stopped treatment because of adverse effects, including five patients who were receiving CC-220 and one patient on placebo, Victoria Werth, MD, of the University of Pennsylvania, Philadelphia, said during a poster presentation at the annual meeting of the Society for Investigative Dermatology. Higher doses of CC-220 were associated with neutropenia, pneumonia, and dermatitis, she reported.
Dr. Victoria Werth
About 79% of patients completed the study, and none stopped because of lack of efficacy, Dr. Werth said. The most common treatment-emergent adverse effects were mild to moderate nausea and diarrhea. However, four patients experienced serious adverse events, including two patients in the placebo group and two patients who developed pneumonia at the highest (0.6 mg per day) CC-220 dose. In the two highest-dose groups, two patients also developed grade 3 neutropenia, one patient developed grade 1 neutropenia, and there were two cases each of dermatitis and urticaria.
CC-220 appeared to improve scores on the CLASI, SELENA-SENDAI, and PGA, Dr. Werth said. Average drops from baseline on the CLASI ranged from 0 (placebo group) to 7 points (0.3 mg every other day), and were 5 points at 0.3 mg daily, 4 points at alternating doses of 0.3 mg and 0.6 mg, and 6 points at the highest dose of 0.6 mg daily. Among patients whose baseline CLASI score was at least 10, mean decreases ranged between 0 (placebo) and 26 points (0.3 mg daily), and average decreases for the other groups were 9 points (0.3 mg every other day and 0.3 mg alternating with 0.6 mg) or 13 points (0.6 mg daily).
Compared with the placebo group, a greater proportion of CC-220 recipients also had at least a 4-point drop on SELENA-SENDAI and tended to improve more on the tender joint count and the swollen joint count, said Dr. Werth. The average drop in mean PGA score ranged between 0 (placebo group) and 0.9 (0.3 mg per day) and did not show a dose-response trend. The relatively small number of patients in this study and some variability in baseline SLE disease activity made it difficult to draw conclusions about dose-response relationships, Dr. Werth noted. However, there were signs of an overall dose-response trend when pooling mean changes in CLASI, tender and swollen joint counts, SELENA-SLEDAI, and PGA scores.
In terms of pharmacodynamics, doses of at least 0.3 mg CC-220 per day were associated with marked decreases in circulating plasmacytoid dendritic cells and B-cell subsets, which began as early as day 29, Dr. Werth said. Cereblon is part of the cullin-ring finger ligase-4 complex, she explained. Previous work has shown that CC-220 binds with high affinity to cereblon, inducing ubiquitination and increased breakdown of the transcription factors IKZF1 and IKZF3. The end result is an altered immune response.
This study includes an optional 2-year extension phase at the three highest doses of CC-220. Celgene also plans a phase IIb proof-of-concept study in a “broader SLE population,” Dr. Werth said.
Celgene funded the study. Dr. Werth disclosed grant or research support from Celgene, Janssen, Biogen, Roche, and Corbus Pharmaceuticals, and consulting or advisory fees from Celgene, Janssen, Genentech, and several other pharmaceutical companies.