Background Macrophages produce pro-inflammatory cytokines such as TNFα, IL-1, and IL-6, and cause joint destruction. High levels of C-C chemokine receptor 1 (CCR1)-expressing macrophages and CCR1 chemokines have been identified in inflamed synovial fluid and tissue. CCR1 is also involved in osteoclast maturation, mobility, and activation. Orally administered CCX354-C 200 mg QD blocked >90% CCR1 in blood monocytes based on ex vivo assays of Alexa647-MIP-1α binding to CCR1 and was safe and well tolerated in Phase 1.
Objectives Primary: Evaluation of safety and tolerability of CCX354-C in RA. Secondary: Evaluation of efficacy based on RA disease response measurements: ACR, DAS28, CRP, and ESR, as well as bone turnover markers.
Methods This was a 160-subject randomized, double-blind, placebo-controlled Phase 2 clinical trial. Subjects had moderate to severe RA, were on stable methotrexate treatment for at least 8 weeks, had ≥8 swollen and tender joint counts (SJC, TJC; 66/68 joints), and CRP >5 mg/L. SJC and TJC, and CRP level eligibility were confirmed prior to dosing on Day 1. Eligible subjects were stratified based on prior use of biologic drugs, and current corticosteroid use. Subjects received double-blind placebo (N=54), 100 mg CCX354-C BID (N=53), or 200 mg CCX354-C QD (N=53) orally for 12 weeks.
Results Baseline characteristics, mean (SD), were: Age 55 (10) years, 84% female, median RA duration 5 years, DAS28-CRP 5.8 (0.8), median CRP 11 mg/L, median ESR 34 mm/hr. 88% were biologics naïve and 55% were current corticosteroid users. CCX354-C was well tolerated by study subjects. No SAEs were reported in the 200 mg QD and placebo groups. Four SAEs not deemed related to CCX354-C (syncope due to blood draw, angina pectoris, MI, temporal lobe epilepsy) were reported in the 100 mg BID group. ACR20 response data were as follows (p-values for 200 mg QD vs. placebo):
CRP decrease at Week 12 was statistically significant (p=0.023) in the 200 mg QD group vs. placebo. ACR50, ACR70, DAS28-CRP, ESR, and ACR component results indicated greatest efficacy in the 200 mg QD dose group. C-telopeptide, procollagen type I N-terminal propeptide, and osteocalcin decreases were more pronounced in the CCX354-C groups compared to placebo and reached statistical significance at several time points. Clinical responders had higher plasma CCX354 concentrations than non-responders.
Conclusions The novel oral CCR1-specific antagonist CCX354-C at 200 mg QD showed clinical and biologic activity, and appears safe and well tolerated in this study. This is the first demonstration of clinical efficacy in RA with a CCR1 inhibitor, consistent with previous in vitro studies and a synovial biopsy study in humans on the effects of CCR1 blockade.
Disclosure of Interest P. P. Tak Consultant for: Abbott Laboratories, Amgen, Arthrogen, AstraZeneca, Bristol Myers Squibb, ChemoCentryx, Johnson & Johnson, Merck, MerckSerono, Novartis, NovImmune, NovoNordisk, Pfizer, Roche/Genentech, Employee of: GlaxoSmithKline, A. Balanescu: None Declared, V. Tseluyko: None Declared, S. Bojin: None Declared, E. Drescher: None Declared, D. Dairaghi Shareholder of: ChemoCentryx, Inc., Employee of: ChemoCentryx, Inc., S. Miao Shareholder of: ChemoCentryx, Inc., Employee of: ChemoCentryx, Inc., V. Marchesin Shareholder of: ChemoCentryx, Inc., Employee of: ChemoCentryx, Inc., J. Jaen Shareholder of: ChemoCentryx, Inc., Employee of: ChemoCentryx, Inc., T. Schall Shareholder of: ChemoCentryx, Inc., Employee of: ChemoCentryx, Inc., P. Bekker Shareholder of: ChemoCentryx, Inc., Employee of: ChemoCentryx, Inc.