CC-220 yielded positive results in phase 2a study of patients with SLE

In a population of patients with lupus, the ubiquitin ligase modulator CC-220 appeared to be generally well-tolerated, with neutropenia and dermatitis seen at the highest doses assessed, according to a study presented at the EULAR Annual Congress.

“All will agree that safer and more efficacious therapies are needed for patients with lupus,” Richard A. Furie, MD, chief of rheumatology at Northwell Health in New York, told Healio Rheumatology. “Realizing the great unmet needs in lupus, there is currently unprecedented drug development activity for both lupus nephritis and ‘extra-renal’ lupus.”

Richard A. Furie

In the randomized, phase 2a study, researchers evaluated 42 patients with at least a 6-month history of systemic lupus erythematosus (SLE) and a baseline of hybrid SELENA-SLEDAI (hSS) score of at least 4. The mean patient age was 47.2 years and 93% were female. Sixty-four percent of patients were white, while 31% were black. The mean duration of SLE the study population was 9.4 years. The following baseline measures were documented: mean baseline hSS score, 6.6; cutaneous lupus area and severity index (CLASI) activity score, 9.8; and patient global assessment score (PGA), 1.3.

Patients were randomly assigned to one of four intensifying doses of CC-220 or matching placebo. The four active treatment regimens were as follows: CC-220 0.3 mg once daily (QD); 0.3 mg QD; 0.3 mg alternating with 0.6 mg QD; and 0.6 mg QD. Patients were randomly assigned at a 4:1 active/placebo ratio in each group for 12 weeks of treatment. Subjects were then monitored for 12 weeks of observational follow-up and/or long-term extension. Patients were permitted to take stable doses of corticosteroids (≤10 mg prednisone or equivalent daily), NSAIDs and antimalarial drugs. The regimens were evaluated for safety through clinical assessment of adverse events (AEs), laboratory measures, electrocardiograms, physical examinations and overall tolerability assessments.

The study was completed by 79% of subjects, while nine of 42 discontinued. Of those who withdrew from the study, six discontinued due to an AE; one in the placebo group and five in the two highest-dose CC-220 groups combined. Lack of efficacy was not the reason for any patient withdrawal. Serious AEs occurred in four subjects, two in the highest CC-220 doses and three in the placebo group.

Other AEs included neutropenia (two with grade 3 neutropenia; one with grade 1); dermatitis (two patients in the highest CC-220 dose group) and urticaria (one patient in the 0.3-mg QD group and one in the 0.6-mg QD dose groups). At Day 85, the C-220 group achieved mean reductions in CLASI activity score ranging from 4.3 to 7.8 vs. an increase of 0.4 in the placebo group. Reductions in hSS score of at least 4 points were attained by more subjects in the CC-220 group (22.2%) vs. the placebo group (12.5%).

“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%, based on the day 85 median percent change from baseline,” Furie said. “An exposure-response analysis demonstrated decreasing B cells, pDCs and neutrophils with increased exposure to CC-220.”

There was a trend toward greater improvement in tender joint count and swollen joint count in the CC-220 groups vs. the placebo group at day 85. Moreover, a trend was observed toward improvement in the PGA score in the CC-220 groups (ranging from -0.5 to -0.9) vs. the placebo group (0).

CC-20 is an oral immunomodulatory component which binds to and regulates cereblon, a constituent of the E3 ubiquitin ligase complex. CC-220 decreases levels of transcription factors known as Ikaros and Ailos, which have been found to increase the risk of lupus.

“This phase 2a study provided important information regarding the biologic effects, the dose-response, safety, and insights into CC-220’s clinical effects on arthritis and skin disease,” Furie said. “It served as a foundation for a larger phase 2b study planned to start later this year.” — by Jennifer Byrne

Reference:

Werth VP, et al. Abstract #SAT0255. Presented at: EULAR Annual Congress; June 14-17, 2017; Madrid.

Disclosure: Furie reports he is a consultant for Celgene.