Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
CCR1 Antagonist CCX354-C in Phase 2 Clinical Development for Rheumatoid Arthritis.
J. Dairaghi, Daniel, Marchesin, Vittorio, A. Johnson, Daniel, Miao, Shichang, C. Seitz, Lisa, Wang, Yu, Zhang, Penglie
CCX354-C is an oral drug targeting the chemokine receptor CCR1, which is instrumental in monocyte/macrophage infiltration into the joints of RA patients. The purpose of the preclinical and clinical studies conducted to date was to determine the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of CCX354-C. This paved the way for a Phase 2 clinical trial in patients with RA.
PK/PD requirements for complete inhibition of CCR1-mediated leukocyte infiltration were defined in rabbits (LPS injection into the knee joint) and rats (thioglycollate-induced sterile peritonitis), following oral dosing of CCX354-C. In the Phase 1 program, 84 male or female healthy volunteers (HVs) received either placebo or CCX354-C orally at doses ranging from 1 to 300 mg in the single-dose study and from 3 to 300 mg/day in the multiple-dose study. In total, 70 HVs received CCX354-C. Blood was collected at pre-specified time points for PK and PD analyses. In the 10, 30, and 100 mg dose cohorts, blood was collected for ex vivo analysis of CCR1 receptor coverage on blood monocytes using a flow-cytometric assay with Alexa647-CCL3. Based on this information, 24 patients with stable RA were randomized to receive either placebo or daily doses of 100 to 200 mg CCX354-C for 14 days. In total, 18 RA patients received CCX354-C. Safety, PK and potential effects on concomitant methotrexate administration were assessed in this study.
CCX354-C blocked chemotaxis of human monocytic cells towards 17 separate RA synovial fluids. In the preclinical models, leukocyte infiltration into inflamed rabbit knee or rat peritoneum was effectively blocked if plasma levels of CCX354 were maintained sufficiently high to produce 90% CCR1 blockade on circulating leukocytes.
CCX354-C was well tolerated, displayed excellent oral bioavailability and dose-proportional increases in exposure in all 3 clinical trials conducted in HVs and RA subjects. No serious adverse events or withdrawals due to adverse events have been observed. Plasma levels as high as 5,000 ng/mL and 3,700 ng/mL were reached in the single and multiple-dose studies, respectively. These levels of CCX354 far exceed those required for CCR1 blockade (e.g., 90% inhibition (IC90) of CCR1-mediated chemotaxis of human monocytes in 100% human plasma required 110 ng/mL). The plasma half-life of the drug approached 7 hours at the 300 mg dose. In the RA study, co-administration of CCX354-C with methotrexate had no influence on the plasma levels of either drug. In the clinical ex vivo PD assay, high levels of receptor coverage (> 90%) at the 12-hour time point were achieved in blood after a single dose of 100 mg CCX354-C.
The oral CCR1-specific antagonist CCX354-C showed an excellent safety and tolerability profile in Phase 1 studies in 70 HVs and 18 RA patients. PK and PD data indicate that daily doses of 200 mg CCX354-C produce greater than 90% receptor coverage in blood at all times. No drug-drug interactions were noted between CCX354-C and methotrexate. Based on results from these clinical trials and supportive preclinical studies, a Phase 2 clinical trial has been initiated in 150 patients with active RA with an inadequate response to methotrexate.
To cite this abstract, please use the following information:
J. Dairaghi, Daniel, Marchesin, Vittorio, A. Johnson, Daniel, Miao, Shichang, C. Seitz, Lisa, Wang, Yu, et al; CCR1 Antagonist CCX354-C in Phase 2 Clinical Development for Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1100