Background/Purpose: CC-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. CC-220 is currently in development for the treatment of SLE as well as other autoimmune conditions and multiple myeloma. This study evaluated the safety, tolerability and pharmacokinetics of CC-220 in subjects with SLE. Exploratory efficacy assessments were included.

Methods: Subjects 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).

Results: A 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. Pharmacokinetic evaluation demonstrated dose proportional exposure between cohorts, with moderate accumulation in the non-alternating dose cohort. An exposure-response analysis demonstrated decreasing B cells, pDCs with increased exposure to CC-220.

Conclusion: CC-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.