In Vitro | In vitro activity: Edicotinib, formerly known as JNJ-40346527, is a novel selective and orally bioavailable inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase. It is undergoing clinical investigation and acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527-treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527-treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527-treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE.
Kinase Assay: Edicotinib, formerly known as JNJ-40346527, is a novel selective and orally bioavailable inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase. |
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In Vivo | Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527-treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527-treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527-treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE. Edicotinib (oral gavage; 3, 10, 30 and 100 mg/kg; 5 days) significantly inhibits microglial proliferation in ME7 mice. It diminishes the number of microglia (total CD45+CD11b+ cells) only at the highest dose tested of 100 mg/kg, and JNJ-527 depletes up to 50% of patrolling blood monocytes at every dose tested (CD45+CD11bhighLy6Cintermediate/lowcells) with only a tendency for a reduction in the proportion of inflammatory monocytes (Ly6C high cells) at 100 mg/kg |
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