title: Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys.
abstract: A strategy to produce sufficient anticoagulant properties with reduced risk of bleeding may be possible through inhibition of factor XI (FXI), a component of the intrinsic coagulation cascade. The objective of this work was to determine the safety profile of ISIS 416858, a 2'-methoxyethoxy (2'-MOE) antisense oligonucleotide inhibitor of FXI, with focus on assessment of bleeding risk. Cynomolgus monkeys administered ISIS 416858 (4, 8, 12, and 40 mg/kg/wk, subcutaneous) for up to 13 weeks produced a dose-dependent reduction in FXI (mRNA in liver and plasma activity) and a concomitant increase in activated partial thromboplastin time (APTT). ISIS 416858 (20 or 40 mg/kg/wk) reduced plasma FXI activity by 80% at 4 weeks of treatment that resulted in a 33% increase in APTT by 13 weeks with no effects on PT, platelets, or increased bleeding following partial tail amputation or gum and skin laceration. The dose-dependent presence of basophilic granules in multiple tissues in ISIS 416858-treated animals was an expected histologic change for a 2'-MOE antisense oligonucleotide, and no toxicity was attributed to hepatic FXI reduction. Basophilic granules reflect cellular drug uptake and subsequent visualization on hematoxylin staining. These results suggest that ISIS 416858 has an acceptable preclinical safety profile and is a promising clinical candidate to treat thrombotic disease.
authors.affiliation: Preclinical Development, ISIS Pharmaceuticals, Carlsbad, CA, USA. hyounis@isisph.com
authors.forename: Husam S
authors.initials: HS
authors.lastname: Younis
authors.forename: Jeff
authors.initials: J
authors.lastname: Crosby
authors.forename: Jung-Im
authors.initials: JI
authors.lastname: Huh
authors.forename: Hong Soo
authors.initials: HS
authors.lastname: Lee
authors.forename: Soyub
authors.initials: S
authors.lastname: Rime
authors.forename: Brett
authors.initials: B
authors.lastname: Monia
authors.forename: Scott P
authors.initials: SP
authors.lastname: Henry
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005172:Factor XI / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006470:Hemorrhage / Q000097:blood / Q000517:prevention & control*; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous; D008252:Macaca fascicularis; D008297:Male; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D010314:Partial Thromboplastin Time; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: C572197:ISIS 416858; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D005172:Factor XI