379 A phase 2, randomized, placebo-controlled, double-blind, ascending dose study to evaluate efficacy, safety, tolerability, pharmacokinetics, pharmacodynamics & pharmacogenetics of CC-220 in subjects with SLE

The efficacy, safety, and tolerability of CC-220, a CUL4CRBN E3 ubiquitin ligase modulator, were evaluated in adults with SLE. Forty-two subjects with baseline (BL) hybrid SELENA-SLEDAI (HSS) score ≥4 were randomized to 1 of 4 escalating doses of CC-220 (0.3mg QOD, 0.3mg QD, 0.3mg alternating with 0.6mg QD, and 0.6mg QD) or matching placebo (PBO) for 12 wks, followed by a 12-wk observational follow-up and/or optional long-term extension. There were 39 females (93%) with a mean age of 47.2 yrs; 64% were White and 31% Black. Mean SLE duration was 9.4 yrs, with mean BL scores of 6.6 (HSS), 1.3 (PGA), and 9.8 (CLASI). About 79% of subjects completed the study; 9/42 subjects discontinued, of which 6 (PBO: n=1; highest CC-220 dose: n=5) were due to an AE. No discontinuations were due to lack of efficacy. Most AEs were mild/moderate. Four subjects had serious AEs (PBO: n=2; highest CC-220 dose: n=2 [pneumonia]); 3 had AEs of neutropenia (grade 3: n=2; grade 1: n=1 in the two highest CC-220 treatment groups). Two subjects had dermatitis (highest CC-220 dose) and 2 had urticaria (0.3mg QD: n=1; 0.6mg QD: n=1).A trend toward improved CLASI, HSS, and PGA scores and SJC/TJC was seen with CC-220 through Day 85. More subjects had ≥4-point reduction in HSS score with CC-220 vs PBO by Day 85 (22.2-50% vs 12.5%). The 0.3mg QD and higher doses resulted in decreased circulating pDCs as early as Day 29, with reduction up to 80% by Day 85. CC-220 was generally well tolerated over 12 wks, with neutropenia and dermatitis noted at the highest doses. A low number of subjects and some BL disease characteristic variability across treatment groups limit the interpretability of dose response.