Novel CCR-1 Antagonist Shows Promise in RA

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.

CHICAGO – The novel oral chemokine receptor 1 antagonist CCX354-C was safe and well tolerated and had encouraging clinical and biologic activity against rheumatoid arthritis in a randomized, controlled, phase II study involving 160 patients.

The primary end point of the study was safety and tolerability, but the findings of clinical efficacy in rheumatoid arthritis (RA) mark a first for a chemokine receptor 1 (CCR1) blocker. Such agents have, however, been previously shown to have activity in in vitro models and in a synovial biopsy study in humans. It is well documented that high levels of CCR1-expressing macrophages and CCR1 chemokines can be found in inflamed synovial fluids and tissues in RA, Dr. Paul P. Tak reported at the annual meeting of the American College of Rheumatology.

In the current study, CCX354-C was given at doses of 100 or 200 mg twice daily. Compared with placebo, the 200-mg dose was associated with the greatest efficacy. ACR20 response rates among day 1 eligible subjects in an intention-to-treat analysis, for example, were 56%, 44%, and 30%, in the 200-mg, 100-mg, and placebo groups, respectively, said Dr. Tak of the division of clinical immunology and rheumatology at the Academic Medical Center of the University of Amsterdam.

Significant differences were also seen between patients given CCX354-C or placebo who were biologics naive; ACR20 response rates in these patients were 62%, 42%, and 27% in the 200-mg, 100-mg, and placebo groups, respectively.

C-reactive protein (CRP) levels decreased with treatment, with significantly greater decreases seen in the 200-mg group, compared with placebo. Levels of C-terminal telopeptide (CTx), procollagen type I N-terminal propepetide (PINP), and osteocalcin decreased significantly more in the treatment groups than in the placebo group at several points during the study, Dr. Tak said.

Study participants had moderate to severe RA and were on stable doses of methotrexate for at least 8 weeks at study entry. All had swollen and tender joint counts of 8 or greater, as well as CRP levels greater than 5 mg/L. Most (84%) were women, and the median age of all participants was 55 years. Median disease duration was 5 years, median DAS28 as determined by CRP level (DAS28-CRP) score was 5.8, median CRP was 11 mg/L, and median erythrocyte sedimentation rate was 34 mm/hr.

Most patients (88%) were biologics naive, and a little more than half (55%) were current corticosteroid users.

No serious adverse events were reported in either the 200-mg group or the placebo group; four serious adverse events occurred in the 100-mg treatment group, but these were not considered to be related to the study drug, Dr. Tak noted.

"To take this altogether, CCX354-C shows promise as an orally delivered CCR-1 antagonist for the treatment of rheumatoid arthritis," he said.

Dr. Tak disclosed that he has financial relationships with Abbott Laboratories, Arthrogen B.V., AstraZeneca, Bristol-Meyers Squibb, GlaxoSmithKline, Merck Pharmaceuticals, MerckSerono, NovoNordisk, Pfizer Inc., and Roche Pharmaceuticals. Several other authors of the study are employed by, or have another type of relationship with ChemoCentryx, which is the maker of CCX354-C.