Compounds and methods for reducing fxi expression

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of FXI RNA in a cell or subject, and in certain instances reducing the amount of FXI protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to prevent, treat, or ameliorate at least one symptom of a thromboembolic condition without a significant increase in a bleeding risk. Such thromboembolic conditions include deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial infarction, stroke, thrombosis associated with chronic kidney disease or end-stage renal disease (ESRD), including thrombosis associated with dialysis, or other procoagulant condition. Such symptoms include decreased blood flow through an affected vessel, death of tissue, and death.

Description

SEQUENCE LISTING[0001]The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0337WOSEQ_ST25.txt, created on Apr. 29, 2019, which is 40 KB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.FIELD[0002]Provided herein are compounds, methods, and pharmaceutical compositions for reducing an amount of Factor XI (FXI) RNA in a cell or animal, and in certain instances reducing the amount of FXI protein in a cell or animal. Such compounds, methods, and pharmaceutical compositions are useful to treat or prevent a thromboembolic condition. In certain embodiments, the compounds, methods, and pharmaceutical compositions are useful to treat or prevent a thromboembolic condition without increasing bleeding risk. Such thromboembolic conditions include deep vein thrombosis, venous or arterial thrombosis, pulmonary embolism, myocardial...

AI Technical Summary

Benefits of technology

The invention provides methods for treating, preventing, or reducing the risk of a thromboembolic condition without increasing the risk of bleeding. This includes individuals who are at risk due to factors such as immobility, surgery, dialysis, malignancy, pregnancy, older age, oral contraceptives, atrial fibrillation, previous thromboembolic condition, chronic inflammatory disease, inherited or acquired prothrombotic clotting disorders, and thrombosis associated with chronic kidney disease or end-stage renal disease. The technical effect is the development of effective treatment options without increasing the risk of bleeding and ensuring better outcomes for individuals with thromboembolic conditions.

Problems solved by technology

Thrombosis is the pathological development of blood clots, and an embolism occurs when a blood clot migrates to another part of the body and interferes with organ function.

Significantly, thromboembolism is a major cause of morbidity affecting over 2 million Americans every year.

Drug therapy using warfarin is further complicated by the fact that warfarin interacts with other medications, including drugs used to treat atrial fibrillation, such as amiodarone.

Because therapy with warfarin is difficult to predict, patients must be carefully monitored in order to detect any signs of anomalous bleeding.

Treatment with heparin may cause an immunological reaction that makes platelets aggregate within blood vessels that can lead to thrombosis.

This side effect is known as heparin-induced thrombocytopenia (HIT) resulting in increased bleeding and requires patient monitoring.

Prolonged treatment with heparin may also lead to osteoporosis.

Rivaroxaban, Dabigatran, and Edoxaban all exhibit increased bleeding, especially increased GI bleeding risk compared to warfarin.

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