Antisense inhibition of coagulation factor XI prolongs APTT without increased bleeding risk in cynomolgus monkeys

Area of Science:

• Pharmacology
• Hemostasis and Thrombosis
• Drug Development

Background:

• Factor XI (FXI) inhibition is a potential strategy for anticoagulation with reduced bleeding risk.
• Antisense oligonucleotides offer a targeted approach to modulate specific coagulation factors.

Purpose of the Study:

• To evaluate the preclinical safety and bleeding risk of ISIS 416858, a 2'-methoxyethoxy (2'-MOE) antisense oligonucleotide inhibitor of FXI.
• To assess the dose-dependent effects of ISIS 416858 on FXI activity and coagulation parameters in vivo.

Main Methods:

• Cynomolgus monkeys were administered ISIS 416858 subcutaneously at doses of 4, 8, 12, and 40 mg/kg/wk for up to 13 weeks.
• Assessed FXI levels (mRNA and plasma activity), activated partial thromboplastin time (APTT), prothrombin time (PT), platelet counts, and bleeding following surgical procedures.
• Histological examination of tissues to identify potential toxicities and drug uptake.

Main Results:

• ISIS 416858 dose-dependently reduced FXI activity and increased APTT.
• Significant reduction in plasma FXI activity (80%) and a 33% increase in APTT were observed at 40 mg/kg/wk by week 13.
• No significant effects on PT, platelets, or increased bleeding were noted, despite dose-dependent presence of expected basophilic granules indicating cellular drug uptake.

Conclusions:

• ISIS 416858 exhibits an acceptable preclinical safety profile.
• The FXI inhibitor demonstrates potential as a clinical candidate for managing thrombotic diseases.
• The observed histological changes (basophilic granules) are consistent with 2'-MOE antisense oligonucleotide pharmacology and not indicative of toxicity.