title: Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.
abstract: The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.
authors: Department of Medical and Clinical Affairs, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Pirow
authors: P
authors: Bekker
authors: Department of Biology, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Daniel
authors: D
authors: Dairaghi
authors: Department of Biology, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Lisa
authors: L
authors: Seitz
authors: Department of Chemistry, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Manmohan
authors: M
authors: Leleti
authors: Department of Biology, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Yu
authors: Y
authors: Wang
authors: Department of Biology, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Linda
authors: L
authors: Ertl
authors: Department of Biology, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Trageen
authors: T
authors: Baumgart
authors: Department of Drug Metabolism and Pharmacokinetics, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Sarah
authors: S
authors: Shugarts
authors: Department of Drug Metabolism and Pharmacokinetics, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Lisa
authors: L
authors: Lohr
authors: Department of Drug Metabolism and Pharmacokinetics, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Ton
authors: T
authors: Dang
authors: Department of Drug Metabolism and Pharmacokinetics, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Shichang
authors: S
authors: Miao
authors: Department of Chemistry, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Yibin
authors: Y
authors: Zeng
authors: Department of Chemistry, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Pingchen
authors: P
authors: Fan
authors: Department of Chemistry, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Penglie
authors: P
authors: Zhang
authors: Department of Medical and Clinical Affairs, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Daniel
authors: D
authors: Johnson
authors: Department of Chemistry, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Jay
authors: J
authors: Powers
authors: Department of Discovery and Research, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Juan
authors: J
authors: Jaen
authors: Department of Discovery and Research, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Israel
authors: I
authors: Charo
authors: Department of Discovery and Research, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, California, United States of America.
authors: Thomas J
authors: TJ
authors: Schall
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D064368:Healthy Volunteers; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D009557:Nipecotic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D020298:U937 Cells
chemical_list: D000814:Aniline Compounds; D009557:Nipecotic Acids; D044087:Receptor, Anaphylatoxin C5a; C000620232:avacopan