title: Preclinical and translational evaluation of coagulation factor IXa as a novel therapeutic target.
abstract: The benefits of novel oral anticoagulants are hampered by bleeding. Since coagulation factor IX (fIX) lies upstream of fX in the coagulation cascade, and intermediate levels have been associated with reduced incidence of thrombotic events, we evaluated the viability of fIXa as an antithrombotic target. We applied translational pharmacokinetics/pharmacodynamics (PK/PD) principles to predict the therapeutic window (TW) associated with a selective small molecule inhibitor (SMi) of fIXa, compound 1 (CPD1, rat fIXa inhibition constant (Ki, 21 nmol/L) relative to clinically relevant exposures of apixaban (rat fXa Ki 4.3 nmol/L). Concentrations encompassing the minimal clinical plasma concentration (C min) of the 5 mg twice daily (BID) dose of apixaban were tested in rat arteriovenous shunt (AVS/thrombosis) and cuticle bleeding time (CBT) models. An I max and a linear model were used to fit clot weight (CW) and CBT. The following differences in biology were observed: (1) antithrombotic activity and bleeding increased in parallel for apixaban, but to a lesser extent for CPD1 and (2) antithrombotic activity occurred at high (>99%) enzyme occupancy (EO) for fXa or moderate (>65% EO) for fIXa. translational PK/PD analysis indicated that noninferiority was observed for concentrations of CPD1 that provided between 86% and 96% EO and that superior TW existed between 86% and 90% EO. These findings were confirmed in a study comparing short interfering (si)RNA-mediated knockdown (KD) modulation of fIX and fX mRNA. In summary, using principles of translational biology to relate preclinical markers of efficacy and safety to clinical doses of apixaban, we found that modulation of fIXa can be superior to apixaban.
authors.affiliation: PPDM Merck & Co., Inc. Rahway New Jersey.
authors.forename: Wendy
authors.initials: W
authors.lastname: Ankrom
authors.affiliation: Discovery Chemistry Merck & Co., Inc. Rahway New Jersey.
authors.forename: Harold B
authors.initials: HB
authors.lastname: Wood
authors.affiliation: Discovery Chemistry Merck & Co., Inc. Rahway New Jersey.
authors.forename: Jiayi
authors.initials: J
authors.lastname: Xu
authors.affiliation: In Vitro Pharmacology Merck & Co., Inc. Kenilworth New Jersey.
authors.forename: Wayne
authors.initials: W
authors.lastname: Geissler
authors.affiliation: PPDM Merck & Co., Inc. Kenilworth New Jersey.
authors.forename: Tom
authors.initials: T
authors.lastname: Bateman
authors.affiliation: PPDM Merck & Co., Inc. Rahway New Jersey.
authors.forename: Manash S
authors.initials: MS
authors.lastname: Chatterjee
authors.affiliation: Discovery Pharmaceutical Sciences Merck & Co., Inc. Rahway New Jersey.
authors.forename: Kung-I
authors.initials: KI
authors.lastname: Feng
authors.affiliation: In Vitro Pharmacology Merck & Co., Inc. Kenilworth New Jersey.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Metzger
authors.affiliation: RNA Therapeutics Merck & Co., Inc. West Point Pennsylvania.
authors.forename: Walter R
authors.initials: WR
authors.lastname: Strapps
authors.affiliation: Genetics and Pharmacogenomics Merck & Co., Inc. Boston Massachusetts.
authors.forename: Marija
authors.initials: M
authors.lastname: Tadin-Strapps
authors.affiliation: Cardiometabolic Disease Merck & Co., Inc. Kenilworth New Jersey.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
authors.affiliation: Cardiometabolic Disease Merck & Co., Inc. Kenilworth New Jersey.
authors.forename: Patrick
authors.initials: P
authors.lastname: Andre
keywords: anticoagulation; factor IX; factor IXa; stroke prevention in atrial fibrillation; thrombosis; translational PK/PD.