Background To evaluate the efficacy, safety and tolerability of CC-220 in subjects with Systemic Lupus Erythematosus [SLE] in a Phase 2, randomised, double-blind, placebo-controlled, ascending dose study

Materials and methods 42 adult SLE subjects with serological and clinical activity for ≥6 months, and a baseline Hybrid SELENA-SLEDAI [HSS] score ≥4 were randomised to one of four escalating doses of CC-220 or matching placebo. The four active treatments included CC-220 0.3 mg QOD, 0.3 mg QD, 0.3 mg alternating with 0.6 mg QD, and 0.6 mg QD, randomised 4:1 active to placebo in each group, for 12 weeks of treatment followed by 12 weeks of observational follow-up, and/or optional long term extension. Stable doses of corticosteroids (≤10 mg prednisone or equivalent daily), non-steroidal anti-inflammatory drugs, and antimalarials were permitted.

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].

Biomarkers, such as expression of Aiolos and Ikaros, and change from baseline in lupus serology markers and cell subsets were also assessed.

Safety assessments included type, frequency, severity, and relationship of adverse events [AEs] to CC-220, laboratory (chemistry, haematology including B cell differentiation and immunoglobulin profiling, inflammatory markers, urinalysis), electrocardiogram [ECG], physical examination and overall tolerability.

Results Baseline subject demographics included 39 women (93%) with a mean age 47.2 ± 10.6 years, and included 64% White, 31% Black, 2% Asian and 2% other races. The mean duration of SLE was 10.3 ± 8.0 years, 88% had arthritis, 78% cutaneous disease, 55% alopecia, 25% mucosal ulcers, and 19% increased DNA binding. Baseline HSS score 6.5 ± 2.5, PGA score 1.28 ± 0.54, and CLASI activity score 8.7 ± 9.7. 16 (42.1%) of the patients were Ro [SS-A] positive, and 15 (35.7%) were positive for antiphospholipid antibodies [aPL], which included lupus anticoagulant [LA], anticardiolipin [aCL] and antiphosphatidylserine [aPS] antibodies.

CC-220 as a Cereblon E3 ubiquitin ligase modulator binds to cereblon and facilitates Ikaros and Aiolos degradation. CC-220 inhibits plasmablast differentiation and reduces Ikaros (IKZF1) and Aiolos (IKZF3) protein levels in B-cells, T-cells, and monocytes.

Efficacy and safety outcomes as well as biomarker parameters are pending.

Conclusions CC-220 is a compound that modulates the Cereblon E3 ubiquitin ligase, resulting in reduction in Ikaros and Aiolos protein levels in B cells, T cells, and monocytes. The efficacy and safety of CC-220 in the treatment of SLE is currently being evaluated in a Phase 2 study.

Acknowledgements Abstract is being presented on behalf of the CC-220 study team.

Trial Registration NCT02185040