L11 - Safety and Efficacy of Oral Chemokine Receptor 1 Antagonist CCX354-C in a Phase 2 Rheumatoid Arthritis Study

Tuesday, November 8, 2011: 3:30 PM
W375c (McCormick Place West)
Paul P. Tak1, Andra Balanescu2, Vira Tseluyko3, Silvia Bojin4, Edit Drescher5, Dan Dairaghi6, Shichang Miao6, Vittorio Marchesin7, Juan Jaen6, Pirow Bekker8 and Thomas J. Schall6, 1EULAR & FOCIS Center of Excellence, AMC/University of Amsterdam, Amsterdam, Netherlands, 2University of Medicine and Pharmacy, Bucharest, Romania, 3City Clinical Hospital, Kharkiv, Ukraine, 4Spitalul Judetean de Urgenta “Dr. Fogolyan Kristof”, Sf. Gheorghe, Romania, 5Veszprém Megyei Csolnoky Ferenc Kórház Nonprofit Zrt., Veszprém, Hungary, 6ChemoCentryx, Inc., Mountain View, CA, 7ChemoCentryx, Mountain View, CA, 8Chemocentryx, Inc., Mountain View, CA
Presentation Number: L11

Background/Purpose: High levels of chemokine receptor 1 (CCR1)-expressing macrophages and CCR1 chemokines (CCL3, CCL5, CCL15 and CCL23) have been reproducibly identified in inflamed RA synovial fluids and tissues. CCR1 is also involved in osteoclast maturation, mobility, and activation. CCX354-C is a potent, orally administered CCR1-specific blocker which previously demonstrated safety and tolerability and excellent oral bioavailability in healthy volunteers and subjects with stable RA.

Method: This is a 160-subject multinational, randomized, double-blind, placebo-controlled Phase 2 RA 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 BID (N=54), 100 mg CCX354-C BID (N=53), or 200 mg CCX354-C QD (N=53) orally for 12 weeks. Safety and tolerability were primary endpoints, and secondary endpoints included RA disease response measurements: ACR, DAS28, CRP, and ESR, as well as bone turnover markers, C-telopeptide (CTx), procollagen type I N-terminal propeptide (PINP), and osteocalcin.

Result:  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):

ACR20 at Week 12

Placebo

100 mg BID

200 mg QD

P-value

ITT, Day 1 Eligible Subjects

30%

44%

56%

p=0.014

ITT, Including Day 1 Ineligible Subjects

39%

43%

52%

p=0.17

Biologics Naïve Subjects

35%

42%

57%

p=0.059

Day 1 Eligible, Biologics Naïve Subjects

27%

42%

62%

p=0.002

CRP decrease at Week 12 was statistically significant (p=0.023) in the 200 mg QD group vs. placebo. ACR50, ACR70, DAS28-CRP, and ACR component results indicate greatest efficacy in the 200 mg QD dose group. CTx, PINP, and osteocalcin decreases were more pronounced in the CCX354-C groups compared to placebo and reached statistical significance at several time points during the study. Clinical responders had higher plasma CCX354 concentrations than non-responders. 

Conclusion: 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 blocker, consistent with previous studies in in vitro models of RA and a synovial biopsy study in humans on the effects of CCR1 blockade.


Keywords: chemokines, clinical trials, macrophages, monocytes and rheumatoid arthritis, treatment

Disclosure: P. P. Tak, Arthrogen b.v., 1, Roche Pharmaceuticals, 2, Roche Pharmaceuticals, 5, Abbott Laboratories, 5, AstraZeneca, 2, AstraZeneca, 5, NovoNordisk, 2, NovoNordisk, 5, Pfizer Inc, 2, Pfizer Inc, 5, Merck Pharmaceuticals, 5, MerckSerono, 2, Bristol-Myers Squibb, 2, Bristol-Myers Squibb, 5, GlaxoSmithKline, 3 ; A. Balanescu, Chemocentryx, 9 ; V. Tseluyko, Chemocentryx, 9 ; S. Bojin, Chemocentryx, 9 ; E. Drescher, Chemocentryx, 9 ; D. Dairaghi, Chemocentryx, 3 ; S. Miao, Chemocentryx, 3 ; V. Marchesin, Chemocentryx, 3 ; J. Jaen, Chemocentryx, 3 ; P. Bekker, Chemocentryx, 3 ; T. J. Schall, Chemocentryx, 3 .