WO2013070771A1

WO2013070771A1 - Administration of factor xi antisense oligonucleotides

Info

Publication number: WO2013070771A1
Application number: PCT/US2012/063951
Authority: WO
Inventors: John Grundy; Sanjay Bhanot; Que Liu
Original assignee: Isis Pharmaceuticals, Inc.
Priority date: 2011-11-07
Filing date: 2012-11-07
Publication date: 2013-05-16
Also published as: AU2012327227A1

Abstract

Disclosed herein are methods of administering pharmaceutical compositions comprising a modified antisense oligonucleotide for decreasing Factor XI activity and decreasing Factor XI antigen. Also disclosed herein are methods of administering pharmaceutical compositions comprising a modified antisense oligonucleotide for treating or preventing thromboembolic and inflammatory disorders in a subject in need thereof. Such pharmaceutical compositions comprising an antisense oligonucleotide targeting Factor XI can also be used as a prophylactic treatment to prevent subjects at risk for thromboembolic and inflammatory conditions.

Description

ADMINISTRATION OF FACTOR XI ANTISENSE OLIGONUCLEOTIDES

Sequence Listing

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0165WOSEQ.txt created November 6, 2012, which is 68 Kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

Field of the Invention

Embodiments described herein provide methods of administering modified antisense oligonucleotides for decreasing Factor XI activity and Factor XI antigen. Also described are methods of administering modified antisense oligonucleotides for treating, preventing, and/or ameliorating thromboembolic and inflammatory disorders in a subject in need thereof. Background of the Invention

Various pharmaceutical compositions, including anticoagulant and anti-inflammatory agents, have been used to ameliorate thromboembolic and inflammatory disorders. Determining an effective therapeutic dose of such drugs remains difficult. For example, the most commonly used anticoagulants, warfarin, heparin, and low molecular weight heparin (LMWH), all possess significant drawbacks.

Warfarin is typically used to treat patients suffering from atrial fibrillation. The drug interacts with vitamin K -dependent coagulation factors which include factors II, VII, IX and X. Anticoagulant proteins C and S are also inhibited by warfarin. 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.

Heparin functions by activating antithrombin which inhibits both thrombin and factor X. (Bjork I, Lindahl U. Mol Cell Biochem. 1982 48: 161-182.) 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) and requires patient monitoring. Prolonged treatment with heparin may also lead to osteoporosis. LMWH can also inhibit Factor 2, but to a lesser degree than unfractioned heparin (UFH). LMWH has been implicated in the development of HIT.

Thus, current anticoagulant agents lack predictability and specificity and, therefore, require careful patient monitoring to prevent adverse side effects, such as bleeding

complications. Administration of such agents in an effective, tolerable amount remains a challenge.

Summary of the Invention

In certain embodiments, disclosed herein are methods of administering to a subject a single dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the single dose comprises an amount of the oligonucleotide in the range of 50-1200 mg; in the range of 40-1440 mg; or in the range of about 50-1200 mg.

In certain embodiments, the single dose is an amount of any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg.

In certain embodiments, the single dose is an amount of any of 40-60 mg, 80-120 mg, 120-180 mg, 160-240 mg, 200-300 mg, 240-360 mg, 280-420 mg, 320-480 mg, 360-540 mg, 400-600 mg, 440-660 mg, 480-720 mg, 520-780 mg, 560-840 mg, 600-900 mg, 640-960 mg, 680-1020 mg, 720-1080 mg, 760-1140 mg, 800-1200 mg, 840-1260 mg, 880-1320 mg, 920-1380 mg, or 960-1440mg.

In certain embodiments, the single dose is an amount of any of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg.

In certain embodiments, the administering decreases Factor XI activity.

In certain embodiments, the administering decreases Factor XI antigen.

In certain embodiments, the administering does not affect PT. In certain embodiments, the administering increases aPTT.

In certain embodiments, the administering does not increase aPTT more than 2 times the upper limit of normal.

In certain embodiments, disclosed herein are methods of administering to a subject a weekly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the weekly dose comprises an amount of the oligonucleotide in the range of 50-300 mg weekly; in the range of 40-360 mg weekly, or in the range of about 50-300 mg weekly.

In certain embodiments, the weekly dose is an amount of any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg.

In certain embodiments, the weekly dose is an amount of any of 40-60 mg, 80-120 mg, 120-180 mg, 160-240 mg, 200-300 mg, or 240-360 mg.

In certain embodiments, the weekly dose is an amount of any of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg. In certain embodiments, a total weekly dose of 50 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 50 mg.

In certain embodiments, a total weekly dose of 40-60 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 40-60 mg.

In certain embodiments, a total weekly dose of about 50 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 50 mg.

In certain embodiments, a total weekly dose of 100 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 100 mg.

In certain embodiments, a total weekly dose of 80-120 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 80-120 mg. In certain embodiments, a total weekly dose of about 100 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 100 mg.

In certain embodiments, a total weekly dose of 150 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 150 mg. In certain embodiments, a total weekly dose of 120-180 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 120-180 mg.

In certain embodiments, a total weekly dose of about 150 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 150 mg. In certain embodiments, a total weekly dose of 200 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 200 mg.

In certain embodiments, a total weekly dose of 160-240 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 160-240 mg.

In certain embodiments, a total weekly dose of about 200 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 200 mg.

In certain embodiments, a total weekly dose of 250 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 250 mg.

In certain embodiments, a total weekly dose of 200-300 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 200-300 mg. In certain embodiments, a total weekly dose of about 250 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 250 mg.

In certain embodiments, a total weekly dose of 300 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 300 mg.

In certain embodiments, a total weekly dose of 240-360 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 240-360 mg.

In certain embodiments, a total weekly dose of about 300 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 300 mg.

In certain embodiments, a total weekly dose of 50 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 50 mg. In certain embodiments, a total weekly dose of 40-60 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 40-60 mg. In certain embodiments, a total weekly dose of about 50 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 50 mg.

In certain embodiments, a total weekly dose of 100 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 100 mg. In certain embodiments, a total weekly dose of 80-120 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 80-120 mg.

In certain embodiments, a total weekly dose of about 100 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 100 mg.

In certain embodiments, a total weekly dose of 150 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 150 mg.

In certain embodiments, a total weekly dose of 120-180 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 120-180 mg.

In certain embodiments, a total weekly dose of about 150 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 150 mg. In certain embodiments, a total weekly dose of 200 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 200 mg.

In certain embodiments, a total weekly dose of 160-240 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 160-240 mg.

In certain embodiments, a total weekly dose of about 200 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 200 mg.

In certain embodiments, a total weekly dose of 250 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 250 mg.

In certain embodiments, a total weekly dose of 200-300 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 200-300 mg. In certain embodiments, a total weekly dose of about 250 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 250 mg. In certain embodiments, a total weekly dose of 300 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 300 mg.

In certain embodiments, a total weekly dose of 240-360 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 240-360 mg.

In certain embodiments, a total weekly dose of about 300 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 300 mg.

In certain embodiments, the administering decreases Factor XI activity.

In certain embodiments, a weekly dose of 100 mg decreases Factor XI activity in the range of 55-65%.

In certain embodiments, a weekly dose of 100 mg decreases Factor XI activity about

60%.

In certain embodiments, a weekly dose of 150 mg decreases Factor XI activity in the range of 65-75%.

In certain embodiments, a weekly dose of 150 mg decreases Factor XI activity about

70%.

In certain embodiments, a weekly dose of 200 mg decreases Factor XI activity in the range of 70-80%.

In certain embodiments, a weekly dose of 200 mg decreases Factor XI activity about

75%.

In certain embodiments, the administering decreases Factor XI antigen. In certain embodiments, the administering does not affect PT. In certain embodiments, the administering increases aPTT.

In certain embodiments, disclosed herein are methods of administering to a subject a biweekly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the bi-weekly dose comprises an amount of the oligonucleotide in the range of 100-600 mg; in the range of 80-720 mg; or in the range of about 100-600 mg.

In certain embodiments, the bi-weekly dose is an amount of any of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. In certain embodiments, the bi-weekly dose is an amount of any of 80-120 mg, 120-180 mg, 160-240 mg, 200-300 mg, 240-360 mg, 280-420 mg, 320-480 mg, 360-540 mg, 400-600 mg, 440-660 mg, or 480-720 mg.

In certain embodiments, the bi-weekly dose is an amount of any of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg.

In certain embodiments, the administering decreases Factor XI activity.

In certain embodiments, the bi-weekly dose of 150 mg decreases Factor XI activity in the range of 45-55%.

In certain embodiments, the bi-weekly dose of 150 mg decreases Factor XI activity about 50%.

In certain embodiments, the bi-weekly dose of 200 mg decreases Factor XI activity in the range of 55-65%.

In certain embodiments, the bi-weekly dose of 200 mg decreases Factor XI activity about

60%. In certain embodiments, the bi-weekly dose of 300 mg decreases Factor XI activity in the range of 65-75%.

In certain embodiments, the bi-weekly dose of 300 mg decreases Factor XI activity about

70%.

In certain embodiments, the bi-weekly dose of 400 mg decreases Factor XI activity in the range of 70-80%.

In certain embodiments, the bi-weekly dose of 400 mg decreases Factor XI activity about

75%. In certain embodiments, the administering decreases Factor XI antigen. In certain embodiments, the administering does not affect PT. In certain embodiments, the administering increases aPTT.

In certain embodiments, disclosed herein are methods of administering to a subject monthly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the monthly dose comprises an amount of the oligonucleotide in the range of 200-1200 mg; in the range of 160- 1440 mg; or in the range of about 200- 1200 mg.

In certain embodiments, the monthly dose is an amount of any of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg.

In certain embodiments, the monthly dose is an amount of any of 160-240 mg, 200-300 mg, 240-360 mg, 280-420 mg, 320-480 mg, 360-540 mg, 400-600 mg, 440-660 mg, 480-720 mg, 520-780 mg, 560-840 mg, 600-900 mg, 640-960 mg, 680-1020 mg, 720-1080 mg, 760-1140 mg, 800-1200 mg, 840-1260 mg, 880-1320 mg, 920-1380 mg, or 960-1440 mg.

In certain embodiments, the monthly dose is an amount of any of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1 150 mg, or about 1200 mg.

In certain embodiments, the administering decreases Factor XI activity.

In certain embodiments, the monthly dose of 200 mg decreases Factor XI activity in the range of 35-45%.

In certain embodiments, the monthly dose of 200 mg decreases Factor XI activity about

40%. In certain embodiments, the monthly dose of 300 mg decreases Factor XI activity in the range of 45-55%.

In certain embodiments, the monthly dose of 300 mg decreases Factor XI activity about

50%.

In certain embodiments, the monthly dose of 400 mg decreases Factor XI activity in the range of 50-60%.

In certain embodiments, the monthly dose of 400 mg decreases Factor XI activity about

55%.

In certain embodiments, the monthly dose of 500 mg decreases Factor XI activity in the range of 55-65%.

In certain embodiments, the monthly dose of 500 mg decreases Factor XI activity about

60%.

In certain embodiments, the monthly dose of 600 mg decreases Factor XI activity in the range of 60-70%.

In certain embodiments, the monthly dose of 600 mg decreases Factor XI activity about

65%.

In certain embodiments, disclosed herein are methods of administering to a subject a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the administering comprises: an induction phase, wherein a dose comprising an amount of the oligonucleotide in the range of 50-1200 mg weekly for 1-15 weeks, and a maintenance phase, wherein a dose comprising an amount of the oligonucleotide in the range of 50-300 mg weekly for at least 1 week.

In certain embodiments, disclosed herein are methods of administering to a subject a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the administering comprises: an induction phase, wherein a dose comprising an amount of the oligonucleotide in the range of 40-1440 mg weekly for 1-15 weeks, and a maintenance phase, wherein a dose comprising an amount of the oligonucleotide in the range of 40-360 mg weekly for at least 1 week. In certain embodiments, disclosed herein are methods of administering to a subject a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the administering comprises: an induction phase, wherein a dose comprising an amount of the oligonucleotide in the range of about 50-1200 mg weekly for 1-15 weeks, and a maintenance phase, wherein a dose comprising an amount of the oligonucleotide in the range of about 50-300 mg weekly for at least 1 week.

In certain embodiments, a total weekly induction phase dose in an amount in the range of 50-1200 mg is administered in 7 equal daily administrations, such that the total weekly induction phase dose does not exceed 50-1200 mg. In certain embodiments, a total weekly induction phase dose in an amount in the range of

40-1440 mg is administered in 7 equal daily administrations, such that the total weekly induction phase dose does not exceed 40-1440 mg.

In certain embodiments, a total weekly induction phase dose in an amount in the range of about 50-1200 mg is administered in 7 equal daily administrations, such that the total weekly induction phase dose does not exceed about 50-1200 mg.

In certain embodiments, a total weekly maintenance phase dose in an amount in the range of 50-300 mg is administered in 7 equal daily administrations, such that the total weekly maintenance phase dose does not exceed 50-300 mg. In certain embodiments, a total weekly maintenance phase dose in an amount in the range of 40-360 mg is administered in 7 equal daily administrations, such that the total weekly maintenance phase dose does not exceed 40-360 mg.

In certain embodiments, a total weekly maintenance phase dose in an amount in the range of about 50-300 mg is administered in 7 equal daily administrations, such that the total weekly maintenance phase dose does not exceed about 50-300 mg.

In certain embodiments, the dose administered during the induction phase is an amount of any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1 150 mg, or 1200 mg administered once weekly.

In certain embodiments, the dose administered during the induction phase is an amount of any of 40-60 mg, 80-120 mg, 120-180 mg, 160-240 mg, 200-300 mg, 240-360 mg, 280-420 mg, 320-480 mg, 360-540 mg, 400-600 mg, 440-660 mg, 480-720 mg, 520-780 mg, 560-840 mg, 600-900 mg, 640-960 mg, 680-1020 mg, 720-1080 mg, 760-1 140 mg, 800-1200 mg, 840-1260 mg, 880-1320 mg, 920-1380 mg, or 960-1440 mg administered once weekly.

In certain embodiments, the dose administered during the induction phase is an amount of any of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1 100 mg, about 1150 mg, or about 1200 mg administered once weekly.

In certain embodiments, the dose administered during the maintenance phase is an amount of any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg administered once weekly. In certain embodiments, the dose administered during the maintenance phase is an amount of any of 40-60 mg, 80-120 mg, 120-180 mg, 160-240 mg, 200-300 mg, or 240-360 mg administered once weekly. In certain embodiments, the dose administered during the maintenance phase is an amount of any of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg administered once weekly.

In certain embodiments, the induction phase is one week. In certain embodiments, the total weekly induction phase dose is divided equally into 3 separate doses administered on separate days.

In certain embodiments, the total weekly maintenance phase dose is divided equally into 3 separate doses administered on separate days.

In certain embodiments, wherein the administering decreases Factor XI activity. In certain embodiments, the administering decreases Factor XI antigen.

In certain embodiments, the administering does not affect PT.

In certain embodiments, the administering increases aPTT.

In certain embodiments, the administering does not increase aPTT more than 2 times the upper limit of normal. In certain embodiments, the nucleic acid encoding human Factor XI is any of SEQ ID

NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

In certain embodiments, the modified antisense oligonucleotide is a single-stranded modified oligonucleotide.

In certain embodiments, at least one internucleoside linkage of the modified antisense oligonucleotide is a modified internucleoside linkage.

In certain embodiments, at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

In certain embodiments, each internucleoside linkage is a phosphorothioate

internucleoside linkage. In certain embodiments, at least one nucleoside of the modified antisense oligonucleotide comprises a modified sugar.

In certain embodiments, at least one modified sugar is a bicyclic sugar. In certain embodiments, each of the at least one bicyclic sugar comprises a 4'- (CH₂)_n-0- 2' bridge, wherein n is 1 or 2.

In certain embodiments, each of the at least one bicyclic sugar comprises a 4'-CH(CH₃)- 0-2' bridge.

In certain embodiments, at least one modified sugar comprises a 2'-0-methoxyethyl moiety.

In certain embodiments, at least one nucleoside of the modified antisense oligonucleotide comprises at least one tetrahydropyran modified nucleoside wherein a tetrahydropyran ring replaces the furanose ring.

In certain embodiments, each of the at least one tetrahydropyran modified nucleoside has the structure:

wherein Bx is an optionally protected heterocyclic base moiety.

In certain embodiments, at least one nucleoside of the modified antisense

oligonucleotide comprises a modified nucleobase.

In certain embodiments, the modified nucleobase is a 5-methylcytosine.

In certain embodiments, each cytosine is a 5-methylcytosine.

In certain embodiments, the modified antisense oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar. In certain embodiments, the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides; a 5' wing segment consisting of five linked nucleosides; a 3' wing segment consisting of five linked nucleosides; wherein the gap segment is positioned immediately adjacent and between the 5' wing segment and the 3 ' wing segment, wherein each nucleoside of each wing segment comprises a 2'-0-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.

In certain embodiments, the modified oligonucleotide consists of 20 linked nucleosides.

In certain embodiments, the nucleobase sequence of the modified antisense

oligonucleotide is 100% complementary to a nucleobase sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

In certain embodiments, the modified antisense oligonucleotide comprises the nucleobase sequence of SEQ ID NO: 5.

In certain embodiments, the modified antisense oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 5.

In certain embodiments, the modified antisense oligonucleotide is ISIS 416858.

In certain embodiments, the modified antisense oligonucleotide comprises the nucleobase sequence of SEQ ID NO: 6.

In certain embodiments, wherein the modified antisense oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 6.

In certain embodiments, the modified antisense oligonucleotide is ISIS 416852.

In certain embodiments, the administering decreases risk of developing a

thromboembolic condition in the subject.

In certain embodiments, the administering treats a thromboembolic condition in the subject. In certain embodiments, the thromboembolic disorder is any of infarct, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke, thrombosis, embolism, thromboembolism, and coronary artery disease (CAD). In certain embodiments, the subject is at risk for developing a thromboembolic disorder due to a risk factor.

In certain embodiments, the risk factor is any of surgery, cancer, malignancy, pregnancy, older age, use of oral contraceptives, immobility, sepsis, having a mechanical heart valve, valvular heart disease, atrial fibrillation, atherosclerosis atrial fibrillation, genetic predisposition, antiphospholipid syndrome, inherited or acquired prothrombotic clotting disorders, and Factor V Leiden.

In certain embodiments, the surgery is orthopedic surgery.

In certain embodiments, the orthopedic surgery is any of hip replacement surgery, knee replacement surgery, hip fracture surgery, leg fracture surgery, arm fracture surgery, and cranial fracture surgery.

In certain embodiments, the surgery is cosmetic surgery.

In certain embodiments, the subject has been determined to be in need of anticoagulation therapy.

In certain embodiments, the administering decreases risk of developing an inflammatory condition in the subject.

In certain embodiments, the administering treats an inflammatory condition in the subject.

In certain embodiments, the inflammatory condition is any of arthritis, colitis, diabetes, sepsis, allergic inflammation, asthma, immunoproliferative disease, antiphospholipid syndrome, graft-related disorder, trauma, autoimmune diseases, surgery-related disorders, rheumatoid arthritis, juvenile rheumatoid arthritis, arthritis uratica, gout, chronic polyarthritis, periarthritis humeroscapularis, cervical arthritis, lumbosacral arthritis, osteoarthritis, psoriatic arthritis, enteropathic arthritis, ankylosing spondylitis, ulcerative colitis, Inflammatory Bowel Disease (IBD), Crohn's Disease, graft versus host disease (GVHD), disorders associated with graft transplantation rejection, chronic rejection, tissue or cell allografts or xenografts, cancers (e.g., lung cancers), benign hyperplasias, lupus erythematosus, lupus nephritis, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, diabetes, good pasture's syndrome, myasthenia gravis, pemphigus, Crohn's disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulcerative colitis, Sjogren's syndrome, rheumatic diseases, polymyositis, scleroderma, psoriasis, and mixed connective tissue disease.

In certain embodiments, the subject is at risk for developing an inflammatory disorder due to a risk factor.

In certain embodiments, the risk factor is any of arthritis, colitis, diabetes, sepsis, allergic inflammation, asthma, immunoproliferative disease, antiphospholipid syndrome, graft-related disorder, trauma, autoimmune diseases, surgery-related disorders, rheumatoid arthritis, juvenile rheumatoid arthritis, arthritis uratica, gout, chronic polyarthritis, periarthritis humeroscapularis, cervical arthritis, lumbosacral arthritis, osteoarthritis, psoriatic arthritis, enteropathic arthritis, ankylosing spondylitis, ulcerative colitis, Inflammatory Bowel Disease (IBD), Crohn's Disease, graft versus host disease (GVHD), disorders associated with graft transplantation rejection, chronic rejection, tissue or cell allografts or xenografts, cancers (e.g., lung cancers), benign hyperplasias, lupus erythematosus, lupus nephritis, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, diabetes, good pasture's syndrome, myasthenia gravis, pemphigus, Crohn's disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulcerative colitis, Sjogren's syndrome, rheumatic diseases, polymyositis, scleroderma, psoriasis, and mixed connective tissue disease.

In certain embodiments, the subject has been determined to be in need of antiinflammatory therapy.

In certain embodiments, the modified antisense oligonucleotide is administered parenterally. In certain embodiments, the parenteral administration is any of subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, and intracranial administration.

In certain embodiments, the parenteral administration is by injection or infusion. In certain embodiments, the pharmaceutical composition is coadministered with any of aspirin, clopidogrel, dipyridamole, heparin, lepirudin, ticlopidine, warfarin, apixaban, rivaroxaban, LOVENOX, and Factor Xa inhibitor or a combination thereof.

In certain embodiments, the pharmaceutical composition is coadministered with 25-45mg of LOVENOX (enoxaparin). In certain embodiments, the pharmaceutical composition is coadministered with 30mg or 40mg of LOVENOX (enoxaparin).

In certain embodiments, the pharmaceutical composition is coadministered with antiplatelet therapy.

In certain embodiments, the anti-platelet therapy is any of ADP receptor inhibitor, NSAID, phosphodiesterase inhibitor, glycoprotein IIB/IIIA inhibitor or adenosine reuptake inhibitor or a combination thereof.

In certain embodiments, the pharmaceutical composition is coadministered with any of NSAIDS, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, tramadol, methotrexate, abatacept, infliximab, cyclophosphamide, azathioprine, corticosteroids, cyclosporin A, aminosalicylates, sulfasalazine, hydroxychloroquine, leflunomide, etanercept, efalizumab, 6-mercapto-purine (6-MP), and tumor necrosis factor-alpha (TNFalpha), cytokine blockers, and antagonists. In certain embodiments, the modified antisense oligonucleotide comprises a portion of at least 8, of at least 9, of at least 10, of at least 11, of at least 12, of at least 13, of at least 14, of at least 15, of at least 16, of at least 17, of at least 18, of at least 19, of at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 1281 to 1307 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified antisense oligonucleotide is at least 90% complementary to SEQ ID NO: 1.

In certain embodiments, the nucleobase sequence of the modified antisense

oligonucleotide is at least 95% complementary to SEQ ID NO: 1. In certain embodiments, the the nucleobase sequence of the modified antisense oligonucleotide is 100% complementary to SEQ ID NO: 1.

In certain embodiments, disclosed herein are pharmaceutical compositions comprising a modified antisense oligonucleotide consisting of the nucleobase sequence

ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a single dose of the pharmaceutical composition, wherein the single dose comprises an amount of the oligonucleotide in the range of 50-1200mg, in the range of 40-1440mg, or in the range of about 50- 1200mg.

TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a single dose of the pharmaceutical composition, wherein the single dose comprises an amount of the oligonucleotide in the range of 50-1200mg, in the range of 40-1440mg, or in the range of about 50- 1200mg. In certain embodiments, disclosed herein are pharmaceutical compositions comprising a modified antisense oligonucleotide consisting of the nucleobase sequence

ACGGCATTGGTGCACAGTTT (SEQ ID NO: 5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a weekly dose of the pharmaceutical composition, wherein the weekly dose comprises an amount of the oligonucleotide in the range of 50-300 mg, in the range of 40-360 mg, or in the range of about 50-300 mg.

TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a weekly dose of the pharmaceutical composition, wherein the weekly dose comprises an amount of the oligonucleotide in the range of 50-300 mg, in the range of 40-360 mg, or in the range of about 50-300 mg.

ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a biweekly dose of the pharmaceutical composition, wherein the bi-weekly dose comprises an amount of the oligonucleotide in the range of 100-600 mg, in the range of 80-720 mg, or in the range of about 100-600 mg.

TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a biweekly dose of the pharmaceutical composition, wherein the bi-weekly dose comprises an amount of the oligonucleotide in the range of 100-600 mg, in the range of 80-720 mg, or in the range of about 100-600 mg. In certain embodiments, disclosed herein are pharmaceutical compositions comprising a modified antisense oligonucleotide consisting of the nucleobase sequence

ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5 -methyl cytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a monthly dose of the pharmaceutical composition, wherein the monthly dose comprises an amount of the oligonucleotide in the range of 200-1200 mg, in the range of 160-1440 mg, or in the range of about 200-1200 mg. In certain embodiments, disclosed herein are pharmaceutical compositions comprising a modified antisense oligonucleotide consisting of the nucleobase sequence

TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a monthly dose of the pharmaceutical composition, wherein the monthly dose comprises an amount of the oligonucleotide in the range of 200-1200 mg, in the range of 160-1440 mg, or in the range of about 200-1200 mg.

ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moiety for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject an induction phase dose of the pharmaceutical composition, wherein the induction phase dose comprises an amount of the oligonucleotide in the range of 50-1200 mg administered weekly for 1-15 weeks, in the range of 40-1440 mg weekly for 1-15 weeks, or in the range of about 50-1200 mg weekly for 1-15 weeks; and a maintenance phase of the pharmaceutical composition, wherein the maintenance phase dose comprises an amount of the oligonucleotide in the range of 50-300 mg weekly for at least 1 week; in the range of 40-360 mg weekly for at least 1 week; or in the range of about 50-1200 mg weekly for 1-15 weeks. In certain embodiments, disclosed herein are pharmaceutical compositions comprising a modified antisense oligonucleotide consisting of the nucleobase sequence

TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moiety for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject an induction phase dose of the pharmaceutical composition, wherein the induction phase dose comprises an amount of the oligonucleotide in the range of 50-1200 mg administered weekly for 1-15 weeks, in the range of 40-1440 mg weekly for 1-15 weeks, or in the range of about 50-1200 mg weekly for 1-15 weeks; and a maintenance phase of the pharmaceutical composition, wherein the maintenance phase dose comprises an amount of the oligonucleotide in the range of 50-300 mg weekly for at least 1 week; in the range of 40-360 mg weekly for at least 1 week; or in the range of about 50-1200 mg weekly for 1-15 weeks. Brief Description of the Figures

Figure 1 : PK model-predicted and observed ISIS 416858 mean plasma concentration versus time profiles from a single and multiple ascending dose (SAD/MAD) study. The PK parameter estimates from the PK model (fit the mean data of the 50 mg, 100 mg, and 200 mg from the multiple ascending dose cohorts of the Phase 1 clinical trials) were calculated. The

corresponding observed and predicted ISIS 416858 plasma concentrations versus time profiles were generated and are presented.

Figure 2: Selected diagnostic plots for NONMEM model. PD parameter estimates from the PK/PD model were calculated based on the mean Factor XI activity (as a percentage of pre-dose levels) versus time data from the 100 mg, 200 mg, and 300 mg single dose cohorts, and the 100 mg and 200 mg MAD cohorts.

Figure 3 : Observed and model predicted mean Factor XI activity (% predose levels) versus time data. The predicted and observed mean Factor XI activity versus time profiles for the 100 mg, 200 mg, and 300 mg of the single ascending dose (SAD) study cohorts, as well as the 100 mg and 200 mg of the MAD study cohorts were generated and are presented. The open circles depict the observed values and the closed circles depict the model-predicted values.

Figures 4 and 5: Model simulated plasma Factor XI activity (% change from the pre-dose levels) with one year of treatment of various ISIS 416858 dosing regimens. Various dose regimens (weekly, bi-weekly, and monthly) were simulated using the developed PK/PD model.

Figures 6 and 7: Diagrams of various dosing schemes. Detailed Description of the Invention

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of "and" and "or" mean "and/or" unless stated otherwise. Furthermore, the use of the term "including" as well as other forms, such as "includes" and "included", is not limiting. Also, terms such as "element" or "component" encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, and treatises, are hereby expressly incorporated by reference for the portions of the document discussed herein, as well as in their entirety. Definitions

Unless specific definitions are provided, the nomenclature utilized in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well known and commonly used in the art. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of subjects. Certain such techniques and procedures may be found for example in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, Pa., 18th edition, 1990 which is hereby incorporated by reference for any purpose. Where permitted, all patents, applications, published applications and other publications, GENBANK Accession Numbers and associated sequence information obtainable through databases such as National Center for Biotechnology Information (NCBI) and other data referred to throughout in the disclosure herein are incorporated by reference for the portions of the document discussed herein, as well as in their entirety.

Unless otherwise indicated, the following terms have the following meanings:

"2'-0-methoxyethyl" (also 2'-MOE and 2'-0(CH₂)₂-OCH₃) refers to an O-methoxy-ethyl modification of the 2' position of a furosyl ring. A 2'-0-methoxyethyl modified sugar is a modified sugar.

"2'-0-methoxyethyl nucleoside" means a nucleoside comprising a 2'-0-methoxyethyl modified sugar moiety.

"5-methylcytosine" means a cytosine modified with a methyl group attached to the 5' position. A 5-methylcytosine is a modified nucleobase.

"About" as applied to dosing amounts means within ±12% of a value. For example, if it is stated, "the dose is an amount in the range of about 50-1200 mg," it is implied that the dose is an amount in the range of 44-1344mg. In another example, if it is stated that the dose is an amount of "about 50 mg," it is implied that the dose can be from 44 mg to 56 mg. "About" as applied to activity levels, antigen levels, expression levels, PT levels, aPTT levels, and the like means within ±7% of a value. For example, if it is stated, "the administering decreases Factor XI activity about 55%," it is implied that Factor XI activity is decreased 48-62%».

"Administered concomitantly" refers to the co-administration of two agents in any manner in which the pharmacological effects of both are manifest in the subject at the same time. Concomitant administration does not require that both agents be administered in a single pharmaceutical composition, in the same dosage form, or by the same route of administration. The effects of both agents need not manifest themselves at the same time. The effects need only be overlapping for a period of time and need not be coextensive.

"Administering" means providing a pharmaceutical composition to a subject, and includes, but is not limited to, administering by a medical professional and self-administering. "Amelioration" refers to a lessening of at least one indicator, sign, or symptom of an associated disease, disorder, or condition. The severity of indicators may be determined by subjective or objective measures, which are known to those skilled in the art.

"Antisense activity" means any detectable or measurable activity attributable to the hybridization of an antisense oligonucleotide to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid (i.e., "target protein").

"Antisense inhibition" means reduction of target nucleic acid levels or target protein levels in the presence of an antisense oligonucleotide complementary to a target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense oligonucleotide.

"Antisense oligonucleotide" means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding segment of a target nucleic acid. Such an antisense oligonucleotide is "targeted to" the target nucleic acid.

"At risk for developing an inflammatory condition" means selecting a subject who due to various genetic, situational, disease, or environmental factors are at risk of developing an inflammatory condition. In certain embodiments, such factors may include, but are not limited to, a familial history of inflammatory disease such as diabetes, colitis or arthritis, exposure to allergens such as pollen, exposure to material such as asbestos or environmental pollutants. Identifying a subject at risk for developing an inflammatory condition may be accomplished by any method including evaluating a subject's medical history and standard clinical tests or assessments.

"At risk for developing a thromboemoblic condition" means selecting a subject who due to various genetic, situational, disease, or environmental factors are at risk of developing a thromboembolic condition. In certain embodiments, such factors may include, but are not limited to, surgery, cancer, malignancy, pregnancy, older age, use of oral contraceptives, immobility, sepsis, having a mechanical heart valve, valvular heart disease, atrial fibrillation, atherosclerosis atrial fibrillation, genetic predisposition, antiphospholipid syndrome, and inherited or acquired prothrombotic clotting disorders, such as Factor V Leiden. Identifying a subject at risk for developing a thromboembolic condition may be accomplished by any method including evaluating a subject's medical history and standard clinical tests or assessments. "Bicyclic sugar" means a furosyl ring modified by the bridging of two non-geminal ring atoms. A bicyclic sugar is a modified sugar.

"Bicyclic nucleic acid" or "BNA" refers to a nucleoside or nucleotide wherein the furanose portion of the nucleoside or nucleotide includes a bridge connecting two carbon atoms on the furanose ring, thereby forming a bicyclic ring system.

"Bi-weekly" means occurring once every other week.

"Cap structure" or "terminal cap moiety" means chemical modifications, which have been incorporated at either terminus of an antisense compound.

"Co-administration" means administration of two or more pharmaceutical agents to a subject. The two or more pharmaceutical agents may be in a single pharmaceutical composition, or may be in separate pharmaceutical compositions. Each of the two ormore pharmaceutical agents may be administered through the same or different routes of administration. Coadministration encompasses parallel or sequential administration.

"Complementarity" means the capacity for pairing between nucleobases of a first nucleic acid and a second nucleic acid. In certain embodiments, the first nucleic acid is an antisense oligonucleotide and the second nucleic acid is a target nucleic acid.

"Contiguous nucleobases" means nucleobases immediately adjacent to each other.

"Diluent" means an ingredient in a pharmaceutical composition that lacks

pharmacological activity, but is pharmaceutically necessary or desirable. For example, the diluent in an injected pharmaceutical composition may be a liquid, e.g. saline solution or phosphate buffered saline (PBS).

"Dose" means a specified quantity of a pharmaceutical agent provided in a single administration, or in a specified time period. In certain embodiments, a dose may be

administered in one, two, or more boluses, tablets, or injections. For example, in certain embodiments where subcutaneous administration is desired, the desired dose requires a volume not easily accommodated by a single injection, therefore, two or more injections may be used to achieve the desired dose. In certain embodiments, the pharmaceutical agent is administered by infusion over an extended period of time or continuously. Doses may be stated as the amount of pharmaceutical agent per hour, day, week, bi-week, or month. In certain embodiments, single dose means admistration of one dose, and only one dose, to a subject. "Dosage unit" means a form in which a pharmaceutical agent is provided. In certain embodiments, a dosage unit is a vial containing lyophilized ISIS 416858. In certain

embodiments, a dosage unit is a vial containing reconstituted ISIS 416858.

"Dosing regimen" is a combination of doses designed to achieve one or more desired effects. In certain embodiments, a dose regimen is designed to provide a therapeutic effect quickly.

"Duration" means the period of time during which an activity or event continues. For example, the duration of an induction phase is the period of time during which induction doses are administered. For example, the duration of the maintenance phase is the period of time during which maintenance doses are administered.

"Effective amount" means the amount of pharmaceutical composition sufficient to effectuate a desired physiological outcome in a subject in need of the agent. The effective amount may vary among subjects depending on the health and physical condition of the subject to be treated, the taxonomic group of the subjects to be treated, the formulation of the pharmaceutical composition, assessment of the subject's medical condition, and other relevant factors.

"Factor 11 nucleic acid" or "Factor XI nucleic acid" or "Fl 1 nucleic acid" or "FXI nucleic acid" mean any nucleic acid encoding Factor XI. For example, in certain embodiments, a Factor XI nucleic acid includes a DNA sequence encoding Factor XI, an RNA sequence transcribed from DNA encoding Factor XI (including, for example, genomic DNA comprising introns and exons), an mRNA sequence encoding Factor XI (including, for example, pre- mRNA), and cDNA derived from RNA. In certain embodiments, a Factor XI nucleic acid is the sequence of GENBANK Accession No. NM_000128.3, incorporated herein as SEQ ID NO: 1 ; the reverse complement of GENBANK Accession No. NT_022792.17, truncated from 19598000 to 19624000, incorporated herein as SEQ ID NO: 2; GENBANK Accession No. NM 028066.1 , incorporated herein as SEQ ID NO: 3; or GENBANK Accession No. NW 001118167.1, incorporated herein as SEQ ID NO: 4. "A nucleic acid encoding human Factor XI" means a Factor XI nucleic acid encoding Factor XI.

"Fully complementary" or "100% complementary" means each nucleobase of a first nucleic acid is capable of precise base pairing with the corresponding nucleobase in a second nucleic acid, i.e., each nucleobase of a first nucleic acid has a complementary nucleobase in a second nucleic acid. In certain embodiments, the first nucleic acid is an antisense oligonucleotide and the second nucleic acid is a target nucleic acid.

"Gapmer" means an antisense oligonucleotide in which an internal region having a plurality of nucleosides that support RNase H cleavage is positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as a "gap segment" and the external regions may be referred to as "wing segments."

"Hybridization" means the annealing of complementary nucleic acid molecules. In certain embodiments, complementary nucleic acid molecules include an antisense

oligonucleotide and a target nucleic acid.

"Immediately adjacent" means there are no intervening elements between the immediately adjacent elements.

"In need of anticoagulant therapy" means selecting a subject in need of anticoagulant therapy. In certain embodiments, a subject may be in need of anticoagulant therapy due to a thromboembolic condition. In certain embodiments, a subject may be in need of anticoagulant therapy due to a risk factor for developing a thromboembolic condition.

"In need of anti-inflammation therapy" means selecting a subject in need of anti- inflammation therapy. In certain embodiments, a subject may be in need of anti-inflammation therapy due to an inflammatory condition. In certain embodiments, a subject may be in need of anti-inflammatory therapy due to a risk factor for developing an inflammatory condition.

"Induction phase" means a dosing phase during which administration is initiated and steady state concentrations of pharmaceutical agents are achieved in a target tissue. For example, an induction phase is a dosing phase during which steady state concentrations of antisense oligonucleotide are achieved in liver.

"Inflammatory condition" means a disease, disorder or condition related to an inflammatory response to injury or stimulus characterized by clinical signs of increased redness (rubor), temperature (calor), swelling (tumor), pain (dolor) and/or loss of function (functio laesa) in a tissue. Examples of such diseases, disorders, and conditions include, but are not limited to, arthritis, colitis, diabetes, sepsis, allergic inflammation, asthma, immunoproliferative disease, antiphospholipid syndrome, graft-related disorder, trauma, autoimmune diseases or surgery- related disorders.

"Internucleoside linkage" refers to the chemical bond between nucleosides.

"Intravenous administration" means administration into a vein.

"ISIS 416858" means a Factor XI reducing agent that is an antisense oligonucleotide having the nucleobase sequence "ACGGCATTGGTGCACAGTTT", incorporated herein as SEQ ID NO: 5, where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprise 2'- O-methoxyethyl moeity. ISIS 416858 is complementary to nucleobases 1288-1307 of the sequence of GENBANK Accession No. NM 000128.3, incorporated herein as SEQ ID NO: 1.

"ISIS 416852" means a Factor XI reducing agent that is an antisense oligonucleotide having the nucleobase sequence "TGGTGCACAGTTTCTGGCAG", incorporated herein as SEQ ID NO: 6, where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5-methylcytosine, and each of nucleosides 1-5 and 16-20 comprise 2'- O-methoxyethyl moeity. ISIS 416852 is complementary to nucleobases 1281-1300 of the sequence of GENBANK Accession No. NM_000128.3, incorporated herein as SEQ ID NO: 1.

"Linked nucleosides" means adjacent nucleosides which are bonded together.

"Maintenance phase" means a dosing phase after target tissue steady state concentrations of pharmaceutical agents have been achieved. For example, a maintenance phase is a dosing phase after which steady state concentrations of antisense oligonucleotide are achieved in liver.

"Mismatch" or "non-complementary nucleobase" refers to the case when a nucleobase of a first nucleic acid is not capable of pairing with the corresponding nucleobase of a second nucleic acid. In certain embodiments, the first nucleic acid is an antisense oligonucleotide and the second nucleic acid is a target nucleic acid.

"Modified internucleoside linkage" refers to a substitution or any change from a naturally occurring internucleoside bond (i.e. a phosphodiester internucleoside bond).

"Modified nucleobase" refers to any nucleobase other than adenine, cytosine, guanine, thymidine, or uracil. An "unmodified nucleobase" means the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C), and uracil (U).

"Modified nucleoside" means a nucleoside having, independently, a modified sugar moiety or modified nucleobase. "Modified nucleotide" means a nucleotide having, independently, a modified sugar moiety, modified internucleoside linkage, or modified nucleobase.

"Modified antisense oligonucleotide" means an oligonucleotide comprising a modified internucleoside linkage, a modified sugar, or a modified nucleobase.

"Modified sugar" refers to a substitution or change from a natural sugar.

"Motif means the pattern of chemically distinct regions in an antisense compound.

"Natural sugar moiety" means a sugar found in DNA (2'-H) or RNA (2'-OH).

"Naturally occurring internucleoside linkage" means a 3' to 5' phosphodiester linkage.

"Nucleic acid" refers to molecules composed of monomelic nucleotides. A nucleic acid includes ribonucleic acids (RNA), deoxyribonucleic acids (DNA), single-stranded nucleic acids, double-stranded nucleic acids, small interfering ribonucleic acids (siRNA), and microRNAs (miRNA).

"Nucleobase" means a heterocyclic moiety capable of pairing with a base of another nucleic acid.

"Nucleobase sequence" means the order of contiguous nucleobases independent of any sugar, linkage, or nucleobase modification.

"Nucleoside" means a nucleobase linked to a sugar.

"Nucleoside mimetic" includes those structures used to replace the sugar or the sugar and the base and not necessarily the linkage at one or more positions of an oligomeric compound such as for example nucleoside mimetics having morpholino, cyclohexenyl, cyclohexyl, tetrahydropyranyl, bicyclo or tricyclo sugar mimetics e.g. non furanose sugar units. Nucleotide mimetic includes those structures used to replace the nucleoside and the linkage at one or more positions of an oligomeric compound such as for example peptide nucleic acids or morpholinos (morpholinos linked by -N(H)-C(=0)-0- or other non-phosphodiester linkage). Sugar surrogate overlaps with the slightly broader term nucleoside mimetic but is intended to indicate

replacement of the sugar unit (furanose ring) only. The tetrahydropyranyl rings provided herein are illustrative of an example of a sugar surrogate wherein the furanose sugar group has been replaced with a tetrahydropyranyl ring system.

"Nucleotide" means a nucleoside having a phosphate group covalently linked to the sugar portion of the nucleoside. "Oligonucleotide" means a polymer of linked nucleosides each of which can be modified or unmodified, independent one from another.

"Parenteral administration" means administration through injection or infusion.

Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, and intraperitoneal administration

"Pharmaceutical agent" means the substance or substances in a pharmaceutical composition that provide a therapeutic benefit when administered to a subject. For example, in certain embodiments an antisense oligonucleotide targeted to Factor XI is a pharmaceutical agent.

"Pharmaceutical composition" means a mixture of substances suitable for administering to a subject. For example, a pharmaceutical composition may comprise one or more antisense oligonucleotide and a sterile aqueous solution.

"Pharmaceutically acceptable salts" means physiologically and pharmaceutically acceptable salts of antisense compounds, i.e., salts that retain the desired biological activity of the parent antisense oligonucleotide and do not impart undesired toxicological effects thereto.

"Phosphorothioate linkage" means a linkage between nucleosides where the

phosphodiester bond is modified by replacing one of the non-bridging oxygen atoms with a sulfur atom. A phosphorothioate linkage (P=S) is a modified internucleoside linkage.

"Prevent" refers to delaying or forestalling the onset or development of a disease, disorder, or condition for a period of time from minutes to indefinitely. Prevent also means reducing risk of developing a disease, disorder, or condition.

"Prodrug" means a therapeutic agent that is prepared in an inactive form that is converted to an active form within the body or cells thereof by the action of endogenous enzymes or other chemicals or conditions.

"Side effects" means physiological responses attributable to a treatment other than the desired effects. In certain embodiments, side effects include injection site reactions, liver function test abnormalities, renal function abnormalities, liver toxicity, renal toxicity, central nervous system abnormalities, myopathies, and malaise. For example, increased

aminotransferase levels in serum may indicate liver toxicity or liver function abnormality. For example, increased bilirubin may indicate liver toxicity or liver function abnormality. "Single-stranded oligonucleotide" means an oligonucleotide which is not hybridized to a complementary strand.

"Specifically hybridizable" refers to an antisense compound having a sufficient degree of complementarity between an antisense oligonucleotide and a target nucleic acid to induce a desired effect, while exhibiting minimal or no effects on non-target nucleic acids under conditions in which specific binding is desired, i.e. under physiological conditions in the case of in vivo assays and therapeutic treatments.

"Subcutaneous administration" means administration just below the skin.

"Subject" means a human selected for treatment or therapy.

"Targeting" or "targeted" or "targeted to" means the process of design and selection of an antisense oligonucleotide that will specifically hybridize to a target nucleic acid and induce a desired effect.

"Target nucleic acid" all refer to a nucleic acid capable of being targeted by antisense oligonucleotides. "Target protein" is a protein encoded by a target nucleic acid.

"Thromboembolic condition" means any disease, disorder, or condition involving an embolism caused by a thrombus. Examples of such diseases, disorders, and conditions include, but are not limited to, thrombosis, embolism, thromboembolism, infarct, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and coronary artery disease (CAD).

"Treat" refers to administering a pharmaceutical composition to effect an alteration or improvement of a disease, disorder, or condition.

"Unmodified nucleotide" means a nucleotide composed of naturally occuring

nucleobases, sugar moieties, and internucleoside linkages. In certain embodiments, an unmodified nucleotide is an RNA nucleotide (i.e. β-D-ribonucleosides) or a DNA nucleotide (i.e. β-D-deoxyribonucleoside).

Certain Pharmaceutical Compositions

In certain embodiments, the present invention provides pharmaceutical compositions comprising one or more different oligonucleotides. In certain embodiments, pharmaceutical compositions comprise an antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI. In certain embodiments, such pharmaceutical compositions comprise ISIS

416858. ISIS 416858 is a pharmaceutical agent that, when administered to a subject, results in a dose-dependent decrease of Factor XI. ISIS 416858 is efficacious when administered alone and when co-administered with another anticoagulant, anti-platelet, or anti-inflammatory therapeutic. In certain embodiments, pharmaceutical compositions comprise an antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI. In certain embodiments, such pharmaceutical compositions comprise ISIS 416852. ISIS 416852 is a pharmaceutical agent that, when administered to a subject, results in a dose-dependent decrease of Factor XI. ISIS 416852 is efficacious when administered alone and when co-administered with another anticoagulant, anti-platelet, or anti-inflammatory therapeutic.

In certain embodiments, pharmaceutical compositions comprise an antisense

oligonucleotide complementary to a target nucleic acid. In certain embodiments, a sufficient number of nucleobases of the antisense oligonucleotide are capable of hydrogen bonding with corresponding nucleobases in a target nucleic acid such that a desired effect occurs. In certain embodiments, a desired effect is antisense inhibition of a target nucleic acid. In certain embodiments, a desired effect is antisense inhibition of Factor XI nucleic acid. In certain embodiments, a desired effect is a decrease in target protein. In certain embodiments, the target protein is Factor XI. In certain embodiments, a desired effect is a decrease in Factor XI activity. In certain embodiments, a desired effect is a decrease in Factor XI antigen. In certain

embodiments, a desired effect is a decrease in aPTT. In certain embodiments, a desired effect is a decrease in aPTT with no effect on PT. In certain embodiments, a nucleic acid encoding human Factor XI is Factor XI mRNA. In certain embodiments, Factor XI mRNA may or may not include some or all exons. In certain embodiments, least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76 %, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% of the nucleobases of an antisense oligonucleotide are capable of hydrogen bonding with a

corresponding nucleobase of a target nucleic acid. In certain embodiments, 100% of the nucleobases of an antisense oligonucleotide are capable of hydrogen bonding with a

corresponding nucleobase of a target nucleic acid. In certain embodiments, antisense

oligonucleotides are fully complementary (i.e., 100% complementary) to a target nucleic acid. In certain embodiments, antisense oligonucleotides are fully complementary to a nucleic acid encoding Factor XI.

Percent complementarity of an antisense oligonucleotide with a target nucleic acid can be determined using routine methods. For example, an antisense oligonucleotide in which 18 of 20 nucleobases of the antisense oligonucleotide are complementary represents 90 percent complementarity. In this example, the remaining noncomplementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, an antisense oligonucleotide which is 18 nucleobases in length having 4 (four) noncomplementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid has 77.8% overall

complementarity with the target nucleic acid. Percent complementarity of an antisense oligonucleotide with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410; Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology, sequence identity or complementarity, can be determined by, for example, the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482 489).

Non-complementary nucleobases between an antisense oligonucleotide and a Factor XI target nucleic acid may be tolerated provided that the antisense oligonucleotide remains able to specifically hybridize to a target nucleic acid. Moreover, an antisense oligonucleotide may hybridize over one or more segments of a Factor XI nucleic acid such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure, mismatch or hairpin structure).

In certain embodiments, the antisense oligonucleotides provided herein, or specified portions thereof, are fully complementary (i.e., 100% complementary) to a target nucleic acid, or specified portion thereof. For example, an antisense oligonucleotide may be fully

complementary to a Factor XI nucleic acid. For example, a 20 nucleobase antisense

oligonucleotide is fully complementary to a target sequence that is 400 nucleobases long, so long as there is a corresponding 20 nucleobase portion of the target nucleic acid that is fully complementary to the antisense oligonucleotide. Fully complementary can also be used in reference to a specified portion of the first and /or the second nucleic acid. For example, a 20 nucleobase portion of a 30 nucleobase antisense oligonucleotide can be "fully complementary" to a target sequence that is 400 nucleobases long. The 20 nucleobase portion of the 30 nucleobase oligonucleotide is fully complementary to the target sequence (e.g., target nucleic acid) if the target sequence has a corresponding 20 nucleobase portion wherein each nucleobase is complementary to the 20 nucleobase portion of the antisense oligonucleotide. At the same time, the entire 30 nucleobase antisense oligonucleotide may or may not be fully complementary to the target sequence, depending on whether the remaining 10 nucleobases of the antisense compound are also complementary to the target sequence.

The location of a non-complementary nucleobase may be at the 5' end or 3' end of the antisense compound. Alternatively, the non-complementary nucleobase or nucleobases may be at an internal position of the antisense compound. When two or more non-complementary nucleobases are present, they may be contiguous (i.e. linked) or non-contiguous. In one embodiment, a non-complementary nucleobase is located in the wing segment of a gapmer antisense oligonucleotide.

In certain embodiments, antisense oligonucleotides that are, or are up to 12, 13, 14, 15,

16, 17, 18, 19, or 20 nucleobases in length comprise no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a Factor XI nucleic acid, or specified portion thereof.

In certain embodiments, antisense oligonucleotides that are, or are up to 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length comprise no more than 6, no more than 5, no more than 4, no more than 3, no more than 2, or no more than 1 non-complementary nucleobase(s) relative to a target nucleic acid, such as a Factor XI nucleic acid, or specified portion thereof.

The antisense oligonucleotides provided herein also include those which are

complementary to a portion of a target nucleic acid. As used herein, "portion" refers to a defined number of contiguous (i.e. linked) nucleobases within a target nucleic acid. A "portion" can also refer to a defined number of contiguous nucleobases of an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotides are complementary to at least an 8 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least a 9 nucleobase portion of a target nucleic acid. In certain

embodiments, the antisense oligonucleotides are complementary to at least a 10 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least an 1 1 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least a 12 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least a 13 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least a 14 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least a 15 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least a 16 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides, are complementary to at least a 17 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least an 18 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least a 19 nucleobase portion of a target nucleic acid. In certain embodiments, the antisense oligonucleotides are complementary to at least a 20 nucleobase portion of a target nucleic acid.

In certain embodiments, antisense oligonucleotides have a nucleobase sequence that, when written in the 5' to 3' direction, comprises the reverse complement of a target nucleic acid to which it is targeted. In certain embodiments, antisense oligonucleotides are 12 to 30 nucleosides in length, i.e., the antisense oligonucleotides are from 12 to 30 linked nucleosides. In certain embodiments, antisense oligonucleotides are 15 to 25 nucleosides in length. In certain embodiments, antisense oligonucleotides are 17 to 23 nucleosides in length. In certain embodiments, antisense oligonucleotides are 18 to 22 nucleosides in length. In certain embodiments, antisense oligonucleotides are 19 to 21 nucleosides in length. In certain embodiments, antisense oligonucleotides are 20 nucleosides in length. In certain embodiments, the antisense oligonucleotides are 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30 linked nucleosides in length, or a range defined by any two of the above values.

In certain embodiments, antisense oligonucleotides are modified. In certain

embodiments, modified antisense oligonucleotides comprise chemical modifications. In certain embodiments, modifications to antisense oligonucleotides encompass substitutions or changes to intemucleoside linkages, sugar moieties, and/or nucleobases. Modified antisense

oligonucleotides have desirable properties, such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, and/or increased inhibitory activity.

In certain embodiments, antisense oligonucleotides comprise one or more modified, i.e. non-naturally occurring, intemucleoside linkages. In certain embodiments, antisense

oligonucleotides having modified intemucleoside linkages include intemucleoside linkages that retain a phosphorus atom as well as intemucleoside linkages that do not have a phosphorus atom. Representative phosphorus containing intemucleoside linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and

phosphorothioates. Methods of preparation of phosphorous-containing and non-phosphorous- containing linkages are well known.

In certain embodiments, antisense oligonucleotides comprise one or more modified intemucleoside linkages. In certain embodiments, the modified intemucleoside linkages are phosphorothioate linkages. In certain embodiments, each intemucleoside linkage of an antisense oligonucleotide is a phosphorothioate intemucleoside linkage.

In certain embodiments, antisense oligonucleotides comprise one or more nucleosides comprising modified sugar moieties. In certain embodiments, the furanosyl sugar ring of a nucleoside is modified in a number of ways including, but not limited to: addition of a substituent group, particularly at the 2' position; bridging of two non-geminal ring atoms to form a bicyclic nucleic acid (BNA); and substitution of an atom or group such as -S-, -N(R)- or - C(R1)(R2) for the ring oxygen at the 4'-position. In certain embodiments, modified sugars include, but are not limited to: substituted sugars, especially 2 '-substituted sugars having a 2'-F, 2'-OCH2 (2'-OMe) or a 2'-0(CH2)2-OCH3 (2'-0-methoxyethyl or 2'-MOE) substituent group; and bicyclic modified sugars (BNAs), having a 4'-(CH2)n-0-2' bridge, where n=l or n=2.

Methods for the preparations of modified sugars are well known to those skilled in the art.

In certain embodiments, antisense oligonucleotides comprise one or more nucleosides comprising modified nucleobases. Nucleobase (or base) modifications or substitutions are structurally distinguishable from, yet functionally interchangeable with, naturally occurring or synthetic unmodified nucleobases. Both natural and modified nucleobases are capable of participating in hydrogen bonding. Modified nucleobases include synthetic and natural nucleobases such as, for example, 5-methylcytosine (5-me-C). In certain embodiments, modified nucleobases include, but are not limited to, 5-methylcytosine (5-meC). Additional modified nucleobases include 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2- aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5- halouracil and cytosine, 5-propynyl (-C≡C-CH3) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5 -uracil (pseudouracil), 4- thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine.

Heterocyclic base moieties may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2- aminopyridine and 2-pyridone. Nucleobases that are particularly useful for increasing the binding affinity of antisense compounds include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2 aminopropyladenine, 5-propynyluracil and 5- propynylcytosine.

In certain embodiments, antisense oligonucleotides comprise one or more modified nucleobases. In certain embodiments, the modified nucleobase is 5-methylcytosine. In certain embodiments, each cytosine is a 5-methylcytosine.

In certain embodiments, antisense oligonucleotides have chemically modified subunits arranged in patterns, or motifs, to confer to the antisense oligonucleotides properties such as enhanced the inhibitory activity, increased binding affinity for a target nucleic acid, or resistance to degradation by in vivo nucleases.

Chimeric antisense oligonucleotides typically contain at least one region modified so as to confer increased resistance to nuclease degradation, increased cellular uptake, increased binding affinity for the target nucleic acid, and/or increased inhibitory activity. A second region of a chimeric antisense oligonucleotide may optionally serve as a substrate for the cellular endonuclease RNase H, which cleaves the RNA strand of an RNA:DNA duplex.

Antisense oligonucleotides having a gapmer motif are considered chimeric antisense oligonucleotides. In a gapmer an internal region having a plurality of nucleosides that supports RNaseH cleavage is positioned between external regions having a plurality of nucleosides that are chemically distinct from the nucleosides of the internal region. In the case of an antisense oligonucleotide having a gapmer motif, the gap segment generally serves as the substrate for endonuclease cleavage, while the wing segments comprise modified nucleosides. In certain embodiments, the regions of a gapmer are differentiated by the types of sugar moieties comprising each distinct region. The types of sugar moieties that are used to differentiate the regions of a gapmer may in some embodiments include β-D-ribonucleosides, β-D- deoxyribonucleosides, 2'-modified nucleosides (such 2 '-modified nucleosides may include 2'- MOE, and 2'-0-CH₃, among others), and bicyclic sugar modified nucleosides (such bicyclic sugar modified nucleosides may include those having a 4'-(CH2)n-0-2' bridge, where n=l or n=2). In certain embodiments, each distinct region comprises uniform sugar moieties. The wing-gap-wing motif is frequently described as "X-Y-Z", where "X" represents the length of the 5' wing region, "Y" represents the length of the gap region, and "Z" represents the length of the 3' wing region. As used herein, a gapmer described as "X-Y-Z" has a configuration such that the gap segment is positioned immediately adjacent each of the 5' wing segment and the 3' wing segment. Thus, no intervening nucleosides exist between the 5' wing segment and gap segment, or the gap segment and the 3' wing segment. Any of the antisense oligonucleotides described herein can have a gapmer motif. In some embodiments, X and Z are the same, in other embodiments they are different. In a preferred embodiment, Y is between 8 and 15 nucleotides. X, Y or Z can be any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30 or more nucleotides. Thus, gapmers of the present invention include, but are not limited to, for example 5-10-5, 4-8-4, 4-12-3, 4-12-4, 3-14-3, 2-13-5, 2-16-2, 1-18-1 , 3-10-3, 2-10-2, 1-10-1, 2- 8-2, 5-8-5, or 6-8-6.

Antisense oligonucleotides may be admixed with pharmaceutically acceptable active or inert substances for the preparation of pharmaceutical compositions or formulations.

Compositions and methods for the formulation of pharmaceutical compositions are dependent upon a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

An antisense oligonucleotide can be utilized in pharmaceutical compositions by combining the antisense oligonucleotide with a suitable pharmaceutically acceptable diluent. A pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS). PBS is a diluent suitable for use in compositions to be delivered parenterally. Accordingly, in one embodiment, employed in the methods described herein is a pharmaceutical composition comprising an antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI and a pharmaceutically acceptable diluent. In certain embodiments, the pharmaceutically acceptable diluent is PBS. In certain embodiments, the antisense oligonucleotide has the nucleobase seqeunce of SEQ ID NO: 5. In certain embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase seqeunce of SEQ ID NO: 6. In certain embodiments, the antisense oligonucleotide is ISIS 416852.

Pharmaceutical compositions comprising antisense oligonucleotides encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to a subject is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense oligonucleotides, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.

A prodrug can include the incorporation of additional nucleosides at one or both ends of an antisense oligonucleotide which are cleaved by endogenous nucleases within the body, to form the active antisense oligonucleotide.

In certain embodiments, pharmaceutical compositions described herein comprise one or more antisense oligonucleotide and one or more diluent. In certain embodiments, diluents are selected from water, salt solutions, saline, phosphate buffered saline (PBS), alcohol,

polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulosem, and polyvinylpyrrolidone. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain

embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 6. In certain

embodiments, the antisense oligonucleotide is ISIS 416852.

In certain embodiments, pharmaceutical compositions described herein are prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping, or tabletting processes.

In certain embodiments, pharmaceutical compositions described herein are liquids (e.g., a suspension, elixir, and/or solution). In certain embodiments, a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, saline, phosphate buffered saline, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.

In certain embodiments, pharmaceutical compositions described herein are solids (e.g., a powder, tablet, and/or capsule). In certain embodiments, a solid pharmaceutical composition comprising one or more antisense oligonucleotides is prepared using ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.

In certain embodiments, pharmaceutical compositions described herein are formulated as a depot preparation. Certain depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain

embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

In certain embodiments, pharmaceutical compositions described herein comprise a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical

compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimcthylsulfoxidc arc used.

In certain embodiments, pharmaceutical compositions described herein comprise one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents described herein to specific tissues or cell types. For example, in certain embodiments, pharmaceutical compositions include liposomes coated with a tissue-specific antibody.

In certain embodiments, pharmaceutical compositions described herein comprise a co- solvent system. Certain co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.

Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

In certain embodiments, pharmaceutical compositions described herein comprise a sustained-release system. A non-limiting example of such a sustained-release system is a semipermeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks, or months.

In certain embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain embodiments, a pharmaceutical composition comprises a diluent and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.

Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.

Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.

In certain embodiments, pharmaceutical compositions described herein comprise an antisense oligonucleotide in a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate, or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain

embodiments, the antisense oligonucleotide is ISIS 416852.

In certain embodiments, one or more antisense oligonucleotides described herein are formulated as a prodrug. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically more active form of the antisense oligonucleotide. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable than is the corresponding active form. In certain instances, a prodrug may have improved solubility compared to the corresponding active form. In certain embodiments, prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility. In certain embodiments, a prodrug is an ester. In certain embodiments, the ester is metabolically hydrolyzed to carboxylic acid upon administration. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoacid) bound to an acid group. In certain embodiments, the peptide is cleaved upon administration to form the corresponding active form.

In certain embodiments, a prodrug is produced by modifying a pharmaceutically active compound such that the active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry A

Biochemical Approach, Oxford University Press, New York, pages 388-392).

In certain embodiments, a pharmaceutical composition comprising one or more pharmaceutical agents described herein is useful for treating conditions or disorders in a mammalian, and particularly in a human, subject. Suitable administration routes include, but are not limited to, parenteral administration (e.g., subcutaneous administration, intraveneous administration, intramuscular administration, intraarterial administration, and intraperitoneal administration). In certain embodiments, pharmaceutical intrathecals are administered to achieve local rather than systemic exposures. For example, pharmaceutical compositions may be injected directly in the area of desired effect (e.g., in the renal or cardiac area).

In certain embodiments, pharmaceutical compositions described herein are administered in the form of a dosage unit (e.g., injection, infusion, etc.). In certain embodiments, such pharmaceutical compositions comprise an antisense oligonucleotide in an amount of any of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 270 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, 1000 mg,

1005 mg, 1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, HOO mg, 1105 mg, l l lO mg, 1115 mg, 1 120 mg, 1 125 mg, 1130 mg, 1 135 mg, 1140 mg, 1145 mg, 1150 mg, 1 155 mg, 1 160 mg, 1 165 mg, 1 170 mg, 1175 mg, 1 180 mg, 1 185 mg, 1 190 mg, 1 195 mg, and 1200 mg. In certain embodiments, such pharmaceutical compositions comprise an antisense oligonucleotide in an amount of any of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 270 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, about 600 mg, about 605 mg, about 610 mg, about 615 mg, about 620 mg, about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg, about 675 mg, about 680 mg, about 685 mg, about 690 mg, about 695 mg, about 700 mg, about 705 mg, about 710 mg, about 715 mg, about 720 mg, about 725 mg, about 730 mg, about 735 mg, about 740 mg, about 745 mg, about 750 mg, about 755 mg, about 760 mg, about 765 mg, about 770 mg, about 775 mg, about 780 mg, about 785 mg, about 790 mg, about 795 mg, about 800 mg, about 805 mg, about 810 mg, about 815 mg, about 820 mg, about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg, about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, about 1000 mg, about 1005 mg, about 1010 mg, about 1015 mg, about 1020 mg, about 1025 mg, about 1030 mg, about 1035 mg, about 1040 mg, about 1045 mg, about 1050 mg, about 1055 mg, about 1060 mg, about 1065 mg, about 1070 mg, about 1075 mg, about 1080 mg, about 1085 mg, about 1090 mg, about 1095 mg, about 1100 mg, about 1105 mg, about 1110 mg, about 1115 mg, about 1 120 mg, about 1125 mg, about 1 130 mg, about 1135 mg, about 1 140 mg, about 1145 mg, about 1150 mg, about 1155 mg, about 1 160 mg, about 1 165 mg, about 1 170 mg, about 1175 mg, about 1180 mg, about 1185 mg, about 1190 mg, about 1195 mg, and about 1200 mg. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 6. In certain embodiments, the antisense oligonucleotide is ISIS 416852.

In certain embodiments, pharmaceutical compositions described herein comprise a dose of antisense oligonucleotide in an amount in the range of 50-1200 mg, 50-100 mg, 50-150 mg, 50-200 mg, 50-250 mg, 50-300 mg, 50-350 mg, 50-400 mg, 50-450 mg, 50-500 mg, 50-550 mg, 50-600 mg, 50-650 mg, 50-700 mg, 50-750 mg, 50-800 mg, 50-850 mg, 50-900 mg, 50-950 mg, 50- 1000 mg, 50- 1050 mg, 50- 1 100 mg, 50- 1150 mg, 50- 1200 mg, 100- 150 mg, 100-200 mg, 100-250 mg, 100-300 mg, 100-350 mg, 100-400 mg, 100-450 mg, 100-500 mg, 100-550 mg, 100-600 mg, 100-650 mg, 100-700 mg, 100-750 mg, 100-800 mg, 100-850 mg, 100-900 mg, 100-950 mg, 100-1000 mg, 100-1050 mg, 100-1 100 mg, 100-1150 mg, 100-1200 mg, 150-200 mg, 150-250 mg, 150-300 mg, 150-350 mg, 150-400 mg, 150-450 mg, 150-500 mg, 150-550 mg, 150-600 mg, 150-650 mg, 150-700 mg, 150-750 mg, 150-800 mg, 150-850 mg, 150-900 mg, 150-950 mg, 150-1000 mg, 150-1050 mg, 150-1100 mg, 150-1150 mg, 150-1200 mg, 200- 250 mg, 200-300 mg, 200-350 mg, 200-400 mg, 200-450 mg, 200-500 mg, 200-550 mg, 200- 600 mg, 200-650 mg, 200-700 mg, 200-750 mg, 200-800 mg, 200-850 mg, 200-900 mg, 200- 950 mg, 200-1000 mg, 200-1050 mg, 200-1100 mg, 200-1150 mg, 200-1200 mg, 250-300 mg, 250-350 mg, 250-400 mg, 250-450 mg, 250-500 mg, 250-550 mg, 250-600 mg, 250-650 mg, 250-700 mg, 250-750 mg, 250-800 mg, 250-850 mg, 250-900 mg, 250-950 mg, 250-1000 mg, 250-1050 mg, 250-1100 mg, 250-1150 mg, 250-1 100 mg, 300-350 mg, 300-400 mg, 300-450 mg, 300-500 mg, 300-550 mg, 300-600 mg, 300-650 mg, 300-700 mg, 300-750 mg, 300-800 mg, 300-850 mg, 300-900 mg, 300-950 mg, 300-1000 mg, 300-1050 mg, 300-1 100 mg, 300- 1150 mg, 300-1200 mg, 350-400 mg, 350-450 mg, 350-500 mg, 350-550 mg, 350-600 mg, 350- 650 mg, 350-700 mg, 350-750 mg, 350-800 mg, 350-850 mg, 350-900 mg, 350-950 mg, 350- 1000 mg, 350-1050 mg, 350-1100 mg, 350-1150 mg, 350-1200 mg, 400-450 mg, 400-500 mg, 400-550 mg, 400-600 mg, 400-650 mg, 400-700 mg, 400-750 mg, 400-800 mg, 400-850 mg, 400-900 mg, 400-950 mg, 400-1000 mg, 400-1050 mg, 400-1100 mg, 400-1150 mg, 400-1200 mg, 450-500 mg, 450-550 mg, 450-600 mg, 450-650 mg, 450-700 mg, 450-750 mg, 450-800 mg, 450-850 mg, 450-900 mg, 450-950 mg, 450-1000 mg, 450-1050 mg, 450-1100 mg, 450- 1150 mg, 450-1200 mg, 500-550 mg, 500-600 mg, 500-650 mg, 500-700 mg, 500-750 mg, 500- 800 mg, 500-850 mg, 500-900 mg, 500-950 mg, 500-1000 mg, 500-1050 mg, 500-1100 mg, 500-1200 mg, 550-600 mg, 550-650 mg, 550-700 mg, 550-750 mg, 550-800 mg, 550-850 mg, 550-900 mg, 550-950mg, 550-1000 mg, 550-1050 mg, 550-1100 mg, 550-1150 mg, 550-1200 mg, 600-650 mg, 600-700 mg, 600-750 mg, 600-800 mg, 600-850 mg, 600-900 mg, 600-950 mg, 600-1000 mg, 600-1050 mg, 600-1100 mg, 600-1150 mg, 600-1200 mg, 650-700 mg, 650- 750 mg, 650-800 mg, 650-850 mg, 650-900 mg, 650-950 mg, 650-1000 mg, 650-1050 mg, 650- 1100 mg, 650-1150 mg, 650-1200 mg, 700-750 mg, 700-800 mg, 700-850 mg, 700-900 mg, 700-950 mg, 700- 1000 mg, 700- 1050 mg, 700- 1100 mg, 700- 1150 mg, 700- 1200 mg, 750-800 mg, 750-850 mg, 750-900 mg, 750-950 mg, 750-1000 mg, 750-1050 mg, 750-1100 mg, 750- 1150 mg, 750-1200 mg, 800-850 mg, 800-900 mg, 800-950 mg, 800-1000 mg, 800-1050 mg, 800-1100 mg, 800-1150 mg, 800-1200 mg, 850-900 mg, 850-950 mg, 850-1000 mg, 850-1050 mg, 850-1100 mg, 850-1150 mg, 850-1200 mg, 900-950 mg, 900-1000 mg, 900-1050 mg, 900- 1100 mg, 900-1150 mg, 900-1200 mg, 950-1000 mg, 950-1050 mg, 950-1100 mg, 950-1150 mg, 950-1200 mg, 1000-1050 mg, 1000-1100 mg, 1000-1150 mg, 1000-1200 mg, 1050-1100 mg, 1050-1150 mg, 1050-1200 mg, 1100-1150 mg, 1100-1200 mg, and 1150-1200 mg. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 6. In certain

embodiments, the antisense oligonucleotide is ISIS 416852.

In certain embodiments, a pharmaceutical agent is sterile lyophilized antisense oligonucleotide that is reconstituted with a suitable diluent, e.g., sterile water or PBS for injection. The reconstituted product is administered as a subcutaneous injection or as an intravenous infusion after dilution into saline. The lyophilized drug product consists of the antisense oligonucleotide which has been prepared in water for injection, adjusted to pH 7.0-9.0 with acid or base during preparation, and then lyophilized. The lyophilized antisense oligonucleotide may be 5-1200 mg of the antisense oligonucleotide. It is understood that this encompasses 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 1 15 mg,

120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg,

175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg,

230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 270 mg, 280 mg,

285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg,

340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg,

395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg,

450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg,

505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg,

560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg,

615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg,

670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg,

725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg,

780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg,

835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg,

890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg,

945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg,

1000 mg, 1005 mg, 1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1 100 mg, 1105 mg, l l lO mg, 1115 mg, 1120 mg, 1 125 mg, 1 130 mg, 1135 mg, 1 140 mg, 1 145 mg, 1 150 mg, 1 155 mg, 1 160 mg, 1 165 mg, 1 170 mg, 1 175 mg, 1 180 mg, 1 185 mg, 1 190 mg, 1 195 mg, and 1200 mg of lyophilized antisense oligonucleotide. It is also understood that this encompasses about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 270 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, about 600 mg, about 605 mg, about 610 mg, about 615 mg, about 620 mg, about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg, about 675 mg, about 680 mg, about 685 mg, about 690 mg, about 695 mg, about 700 mg, about 705 mg, about 710 mg, about 715 mg, about 720 mg, about 725 mg, about 730 mg, about 735 mg, about 740 mg, about 745 mg, about 750 mg, about 755 mg, about 760 mg, about 765 mg, about 770 mg, about 775 mg, about 780 mg, about 785 mg, about 790 mg, about 795 mg, about 800 mg, about 805 mg, about 810 mg, about 815 mg, about 820 mg, about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg, about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, about 1000 mg, about 1005 mg, about 1010 mg, about 1015 mg, about 1020 mg, about 1025 mg, about 1030 mg, about 1035 mg, about 1040 mg, about 1045 mg, about 1050 mg, about 1055 mg, about 1060 mg, about 1065 mg, about 1070 mg, about 1075 mg, about 1080 mg, about 1085 mg, about 1090 mg, about 1095 mg, about 1 100 mg, about 1105 mg, about 1 110 mg, about 1115 mg, about 1 120 mg, about 1125 mg, about 1130 mg, about 1135 mg, about 1 140 mg, about 1145 mg, about 1 150 mg, about 1155 mg, about 1 160 mg, about 1 165 mg, about 1 170 mg, about 1175 mg, about 1 180 mg, about 1 185 mg, about 1190 mg, about 1195 mg, and about 1200 mg of lyophilized antisense oligonucleotide. The lyophilized drug product may be packaged in a 2 mL Type I, clear glass vial (ammonium sulfate-treated), stoppered with a bromobutyl rubber closure and sealed with an aluminum FLIP-OFF® overseal. In certain embodiments, the lyophilized pharmaceutical agent comprises ISIS 416858. In certain embodiments, the lyophilized pharmaceutical agent comprises ISIS 416852.

The compositions described herein may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions described herein. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.

Antisense oligonucleotides may be covalently linked to one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the antisense oligonucleotides. Typical conjugate groups include cholesterol moieties and lipid moieties. Additional conjugate groups include carbohydrates, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes.

Antisense oligonucleotides can also be modified to have one or more stabilizing groups that are generally attached to one or both termini of antisense compounds to enhance properties such as, for example, nuclease stability. Included in stabilizing groups are cap structures. These terminal modifications protect the antisense oligonucleotide having terminal nucleic acid from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5'-terminus (5'-cap), or at the 3'-terminus (3'-cap), or can be present on both termini. Cap structures are well known in the art and include, for example, inverted deoxy abasic caps. Further 3' and 5'-stabilizing groups that can be used to cap one or both ends of an antisense compound to impart nuclease stability include those disclosed in WO 03/004602 published on January 16, 2003.

Certain Dosing Regimens

In certain embodiments, pharmaceutical compositions are administered according to a dosing regimen. In certain such embodiments, the dosing regimen comprises an induction phase and a maintenance phase. In certain embodiments, the pharmaceutical composition comprises an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 6. In certain embodiments, the antisense oligonucleotide is ISIS 416852.

In certain embodiments, the induction phase includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or more than 20 doses.

In certain embodiments, the induction phase lasts from 1 day to 6 months. In certain embodiments an induction phase lasts 1 day, 2 days, 3, days, 4, days, 5 days, 6 days, or 7 days as measured from administration of the first dose of the induction phase to administration of the first dose of the maintenance phase. In certain embodiments an induction phase lasts 1 week, 2 weeks, 3, weeks, 4, weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, or 26 weeks as measured from

administration of the first dose of the induction phase to administration of the first dose of the maintenance phase. In certain embodiments, the induction phase lasts 1 month, 2 months, 3 months, 4 months, 5 months, or 6 months as measured from administration of the first dose of the induction phase to administration of the first dose of the maintenance phase.

In certain embodiments, the dose administered during the induction phase is lower than the dose administered during the maintenance phase to avoid undesired side effects. In certain embodiments, the undesired side effect is increased liver markers. In certain embodiments, the undesired side effect is increased ALT. In certain embodiments, the undesired side effect is AST. In certain embodiments, the undesired effect is aPTT reduction. In certain embodiments, mild increases in ALT or AST reflect rapid Factor XI lowering activity. In certain embodiments, mild reductions in aPTT reflect rapid Factor XI lowering activity. In certain embodiments, a lower induction phase dose than a maintenance phase dose is desirable for use in treating chronic indications.

In certain embodiments, the dose administered during the induction phase is higher than the dose administered during the maintenance phase to quickly achieve steady state reduction of Factor XI mRNA expression, Factor XI protein expression, Factor XI activity, and/or Factor XI antigen. In certain embodiments, a higher induction phase dose than a maintenance phase dose is desirable for use in treating acute indications.

In certain embodiments where the induction phase includes more than one dose, the doses administered during the induction phase are all the same amount as one another. In certain embodiments, the doses administered during the induction phase are not all the same amount. In certain embodiments, the doses given during the induction phase increase over time. In certain embodiments, the doses given during the induction phase decrease over time.

In certain embodiments, an induction dose is administered by parenteral administration. In certain embodiments, the parenteral administration is subcutaneous administration. In certain embodiments, the parenteral administration is intravenous infusion.

In certain embodiments, the doses administered during the induction phase is an amount in the range of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 1 10 mg, 115 mg,

780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, 1000 mg, 1005 mg, 1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, HOO mg, 1105 mg, l l lO mg, 1115 mg, 1 120 mg, 1125 mg, 1 130 mg, 1135 mg, 1140 mg, 1145 mg, 1150 mg, 1155 mg, 1160 mg, 1165 mg, 1170 mg, 1175 mg, 1180 mg, 1185 mg, 1190 mg, 1195 mg, and 1200 mg. In certain embodiments, the doses administered during the induction phase is an amount in the range of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 270 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, about 600 mg, about 605 mg, about 610 mg, about 615 mg, about 620 mg, about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg, about 675 mg, about 680 mg, about 685 mg, about 690 mg, about 695 mg, about 700 mg, about 705 mg, about 710 mg, about 715 mg, about 720 mg, about 725 mg, about 730 mg, about 735 mg, about 740 mg, about 745 mg, about 750 mg, about 755 mg, about 760 mg, about 765 mg, about 770 mg, about 775 mg, about 780 mg, about 785 mg, about 790 mg, about 795 mg, about 800 mg, about 805 mg, about 810 mg, about 815 mg, about 820 mg, about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg, about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, about 1000 mg, about 1005 mg, about 1010 mg, about 1015 mg, about 1020 mg, about 1025 mg, about 1030 mg, about 1035 mg, about 1040 mg, about 1045 mg, about 1050 mg, about 1055 mg, about 1060 mg, about 1065 mg, about 1070 mg, about 1075 mg, about 1080 mg, about 1085 mg, about 1090 mg, about 1095 mg, about 1100 mg, about 1105 mg, about 1110 mg, about 11 15 mg, about 1120 mg, about 1125 mg, about 1 130 mg, about 1 135 mg, about 1 140 mg, about 1145 mg, about 1150 mg, about 1155 mg, about 1 160 mg, about 1 165 mg, about 1 170 mg, about 1 175 mg, about 1180 mg, about 1185 mg, about 1190 mg, about 1 195 mg, and about 1200 mg.

In certain embodiments, where subcutaneous administration is desired, an induction dose may be administered in two or more subcutaneous injections. In certain embodiments, when the desired induction dose requires a volume not easily accommodated by a single injection, two or more subcutaneous injections may be used to achieve the desired induction dose. In certain embodiments, two or more subcutaneous injections may be used to administer the desired induction dose and minimize or eliminate an undesirable side effect in a subject. In certain embodiments, the undesirable side effect is injection site reaction in the subject.

In certain embodiments, dose, dose frequency, and duration of the induction phase may be selected to achieve a desired effect. In certain embodiments, those variables are adjusted to result in a desired concentration of pharmaceutical agent in a subject. For example, in certain embodiments, dose and dose frequency are adjusted to provide plasma concentration of a pharmaceutical agent at an amount sufficient to achieve a desired effect. In certain embodiments the plasma concentration is maintained above the minimal effective concentration (MEC). In certain embodiments, pharmaceutical compositions described herein are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time. In certain embodiments, the pharmaceutical composition comprises an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 6. In certain

embodiments, the antisense oligonucleotide is ISIS 416852.

In certain embodiments, doses, dose frequency, and duration of the induction phase may be selected to achieve a desired plasma trough concentration of a pharmaceutical composition. In certain embodiments, the pharmaceutical composition comprises an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 6. In certain embodiments, the antisense oligonucleotide is ISIS 416852. In certain embodiments, the desired plasma trough concentration is from 5-100 ng/mL. In certain embodiments, the desired plasma trough concentration is from 5-50 ng/mL. In certain embodiments, the desired plasma trough concentration is from 10-40 ng/mL. In certain embodiments, the desired plasma trough concentration is from 15-35 ng/mL. In certain embodiments, the desired plasma trough concentration is from 20-30 ng/mL.

In certain embodiments, dose, dose frequency, and duration of the induction phase may be selected to achieve a desired effect within 5 to 26 weeks. In certain embodiments, the dose is the same and the dose frequency is varied to achieve the desired effect within 5 to 26 weeks. In certain embodiments, the dose increases over time and the dose frequency remains constant. In certain embodiments, one or more doses of the induction phase are greater than one or more doses of the maintenance phase. In certain embodiments, each of the induction doses is greater than each of the maintenance doses.

In certain embodiments, it is desirable to achieve a desired effect as quickly as possible. In certain embodiments, an induction phase with a high dose and/or high dose frequency may be desirable. Such embodiments may include administration to subjects with an acute condition or in advance of an event, such as, surgery.

In certain embodiments, it is desirable to mitigate an undesired side effect. In certain embodiments, an induction phase with a low dose and/or low dose frequency and/or long duration may be desirable. For example, a long induction phase, with relatively low doses, may result in better tolerance of the pharmaceutical composition. Certain embodiments may result in physiological changes that result in reduced overall side effects. In certain embodiments, such a dose regimen results in reduced liver markers when compared to higher initial doses and/or frequency. In certain embodiments, such a dose regimen results in a gradual decrease in aPTT when compared to higher initial doses and/or frequency. Such embodiments may include gradual increases of dose over time.

In certain embodiments in which a pharmaceutical composition is administered locally, the dosage regimen is selected to achieve a desired local concentration of a pharmaceutical agent as described herein.

In certain embodiments, doses, dose frequency, and duration of the induction phase may be selected to achieve an acceptable safety profile. For example, in certain embodiments, such variables may be selected to mitigate toxicity of the pharmaceutical composition. In certain embodiments, such variables are selected to mitigate liver toxicity. In certain embodiments, such variables are selected to mitigate renal toxicity. In certain embodiments, such variable are selected to mitigate decrease in aPTT. In certain embodiments, doses increase over time. In certain embodiments, one or more doses of the induction phase are lower than one or more doses of the maintenance phase. In certain embodiments, a safety profile is not acceptable when ALT is 5-10 times the upper limit of normal. In certain embodiments, a safety profile is not acceptable when ALT is 5-10 times the upper limit of normal, and bilirubin is elevated two or more times the upper limit of normal. In certain embodiments, an acceptable safety profile comprises ALT elevations that are above three times the upper limit of normal, but do not exceed five times the upper limit of normal. In certain embodiments, an acceptable safety profile comprises ALT elevations that are above three times the upper limit of normal, but do not exceed five times the upper limit of normal, and bilirubin elevations that do not exceed two times the upper limit of normal. In certain embodiments, when administration of a pharmaceutical composition of the invention results in ALT elevations that are above three times the upper limit of normal, the dose and/or dose frequency is adjusted to mitigate the ALT elevation. In certain embodiments, when administration of a pharmaceutical composition of the invention results in ALT elevations that are above three times the upper limit of normal, and bilirubin concentrations that are above two times the upper limit of normal, the dose and/or dose frequency is adjusted to mitigate the ALT elevation and bilirubin elevation. In certain embodiments, the dose and/or dose frequency is adjusted to mitigate the bilirubin elevation alone. In certain embodiments, an acceptable safety profile comprises aPTT reductions that do not increase aPTT more than 2 times the upper limit of normal.

In certain embodiments, the maintenance phase includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,

12, 13, 14, 15, 16, 17, 18, 19, 20, or more than 20 doses.

In certain embodiments, the maintenance phase lasts from one day to the lifetime of the subject. In certain embodiments, the maintenance phase lasts 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days as measured from administration of the last dose of the induction phase to administration of the last dose of the maintenance phase. In certain embodiments, the maintenance phase lasts 1 week, 2 weeks, 3, weeks, 4, weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks, 47 weeks, 48 weeks, 49 weeks, 50 weeks, 51 weeks, or 52 weeks as measured from administration of the last dose of the induction phase to administration of the last dose of the maintenance phase. In certain embodiments, the maintenance phase lasts 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months as measured from administration of the last dose of the induction phase to administration of the last dose of the maintenance phase. In certain embodiments, the maintenance phase lasts 1 year, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, 25 years, 26 years, 27 years, 28 years, 29 years, 30 years, 31 years, 32 years, 33 years, 34 years 35 years, 36 years, 37 years, 38 years, 39 years, 40 years, 41 years, 42 years, 43 years, 44 years, 45 years, 46 years, 47 years, 48 years, 49 years, or 50 years as measured from administration of the last dose of the induction phase to administration of the last dose of the maintenance phase. In certain embodiments the

maintenance phase lasts as long as the dose continues to be needed, effective, and tolerated.

In certain embodiments where the maintenance phase includes more than one dose, the doses administered during the maintenance phase are all the same as one another. In certain embodiments, the doses administered during the maintenance phase are not all the same. In certain embodiments, the doses increase over time. In certain embodiments, the doses decrease over time.

In certain embodiments, a maintenance dose is administered by parenteral administration. In certain embodiments, the parenteral administration is subcutaneous administration. In certain embodiments, the parenteral administration is intravenous infusion.

In certain embodiments, the doses during the maintenance phase are selected 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 1 15 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 270 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg, 330 mg, 335 mg, 340 mg, 345 mg, 350 mg, 355 mg, 360 mg, 365 mg, 370 mg, 375 mg, 380 mg, 385 mg, 390 mg, 395 mg, 400 mg, 405 mg, 410 mg, 415 mg, 420 mg, 425 mg, 430 mg, 435 mg, 440 mg, 445 mg, 450 mg, 455 mg, 460 mg, 465 mg, 470 mg, 475 mg, 480 mg, 485 mg, 490 mg, 495 mg, 500 mg, 505 mg, 510 mg, 515 mg, 520 mg, 525 mg, 530 mg, 535 mg, 540 mg, 545 mg, 550 mg, 555 mg, 560 mg, 565 mg, 570 mg, 575 mg, 580 mg, 585 mg, 590 mg, 595 mg, 600 mg, 605 mg, 610 mg, 615 mg, 620 mg, 625 mg, 630 mg, 635 mg, 640 mg, 645 mg, 650 mg, 655 mg, 660 mg, 665 mg, 670 mg, 675 mg, 680 mg, 685 mg, 690 mg, 695 mg, 700 mg, 705 mg, 710 mg, 715 mg, 720 mg, 725 mg, 730 mg, 735 mg, 740 mg, 745 mg, 750 mg, 755 mg, 760 mg, 765 mg, 770 mg, 775 mg, 780 mg, 785 mg, 790 mg, 795 mg, 800 mg, 805 mg, 810 mg, 815 mg, 820 mg, 825 mg, 830 mg, 835 mg, 840 mg, 845 mg, 850 mg, 855 mg, 860 mg, 865 mg, 870 mg, 875 mg, 880 mg, 885 mg, 890 mg, 895 mg, 900 mg, 905 mg, 910 mg, 915 mg, 920 mg, 925 mg, 930 mg, 935 mg, 940 mg, 945 mg, 950 mg, 955 mg, 960 mg, 965 mg, 970 mg, 975 mg, 980 mg, 985 mg, 990 mg, 995 mg, lOOO mg, 1005 mg,

1010 mg, 1015 mg, 1020 mg, 1025 mg, 1030 mg, 1035 mg, 1040 mg, 1045 mg, 1050 mg, 1055 mg, 1060 mg, 1065 mg, 1070 mg, 1075 mg, 1080 mg, 1085 mg, 1090 mg, 1095 mg, 1 100 mg, 1 105 mg, l l lO mg, 1115 mg, 1120 mg, 1125 mg, 1 130 mg, 1 135 mg, 1140 mg, 1145 mg, 1150 mg, 1155 mg, 1160 mg, 1165 mg, 1 170 mg, 1 175 mg, 1 180 mg, 1185 mg, 1190 mg, 1 195 mg, and 1200 mg. In certain embodiments, the doses administered during the maintenance phase are selected from about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 235 mg, about 240 mg, about 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 270 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 365 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, about 520 mg, about 525 mg, about 530 mg, about 535 mg, about 540 mg, about 545 mg, about 550 mg, about 555 mg, about 560 mg, about 565 mg, about 570 mg, about 575 mg, about 580 mg, about 585 mg, about 590 mg, about 595 mg, about 600 mg, about 605 mg, about 610 mg, about 615 mg, about 620 mg, about 625 mg, about 630 mg, about 635 mg, about 640 mg, about 645 mg, about 650 mg, about 655 mg, about 660 mg, about 665 mg, about 670 mg, about 675 mg, about 680 mg, about 685 mg, about 690 mg, about 695 mg, about 700 mg, about 705 mg, about 710 mg, about 715 mg, about 720 mg, about 725 mg, about 730 mg, about 735 mg, about 740 mg, about 745 mg, about 750 mg, about 755 mg, about 760 mg, about 765 mg, about 770 mg, about 775 mg, about 780 mg, about 785 mg, about 790 mg, about 795 mg, about 800 mg, about 805 mg, about 810 mg, about 815 mg, about 820 mg, about 825 mg, about 830 mg, about 835 mg, about 840 mg, about 845 mg, about 850 mg, about 855 mg, about 860 mg, about 865 mg, about 870 mg, about 875 mg, about 880 mg, about 885 mg, about 890 mg, about 895 mg, about 900 mg, about 905 mg, about 910 mg, about 915 mg, about 920 mg, about 925 mg, about 930 mg, about 935 mg, about 940 mg, about 945 mg, about 950 mg, about 955 mg, about 960 mg, about 965 mg, about 970 mg, about 975 mg, about 980 mg, about 985 mg, about 990 mg, about 995 mg, about 1000 mg, about 1005 mg, about 1010 mg, about 1015 mg, about 1020 mg, about 1025 mg, about 1030 mg, about 1035 mg, about 1040 mg, about 1045 mg, about 1050 mg, about 1055 mg, about 1060 mg, about 1065 mg, about 1070 mg, about 1075 mg, about 1080 mg, about 1085 mg, about 1090 mg, about 1095 mg, about 1100 mg, about 1 105 mg, about 1110 mg, about 11 15 mg, about 1 120 mg, about 1125 mg, about 1130 mg, about 1135 mg, about 1 140 mg, about 1 145 mg, about 1150 mg, about 1155 mg, about 1160 mg, about 1 165 mg, about 1 170 mg, about 1 175 mg, about 1180 mg, about 1185 mg, about 1190 mg, about 1195 mg, and about 1200 mg.

In certain embodiments, where subcutaneous administration is desired, a maintenance dose may be administered in two or more subcutaneous injections. In certain embodiments, when the desired maintenance dose requires a volume not easily accommodated by a single injection, two or more subcutaneous injections may be used to achieve the desired maintenance dose. In certain embodiments, two or more subcutaneous injections may be used to administer the desired induction dose and minimize or eliminate an undesirable side effect in a subject. In certain embodiments, the undesirable side effect is injection site reaction in the subject.

In certain embodiments, doses, dose frequency, and duration of the maintenance phase may be selected to achieve a desired effect. In certain embodiments, those variables are adjusted to result in a desired concentration of pharmaceutical agent in a subject. For example, in certain embodiments, dose and dose frequency are adjusted to provide plasma concentration of a pharmaceutical agent described herein at an amount sufficient to achieve a desired effect. In certain embodiments, the plasma concentration is maintained above the minimal effective concentration (MEC). In certain embodiments, pharmaceutical compositions described herein are administered with a dosage regimen designed to maintain a concentration above the MEC for 10-90% of the time, between 30-90% of the time, or between 50-90% of the time.

In certain embodiments, doses, dose frequency, and duration of the maintenance phase may be selected to achieve a desired plasma trough concentration of a pharmaceutical composition. In certain embodiments, the pharmaceutical composition is an antisense oligonucleotide. In certain embodiments, the desired plasma trough concentration is from 5-100 ng/mL. In certain embodiments, the desired plasma trough concentration is from 5-50 ng/mL. In certain embodiments, the desired plasma trough concentration is from 10-40 ng/mL. In certain embodiments, the desired plasma trough concentration is from 15-35 ng/mL. In certain embodiments, the desired plasma trough concentration is from 20-30 ng/mL. In certain embodiments, doses, dose frequency, and duration of the maintenance phase may be selected to achieve a desired safety profile. For example, in certain embodiments, such variables may be selected to mitigate toxicity of the pharmaceutical composition. In certain embodiments, such variables are selected to mitigate liver toxicity. In certain embodiments, such variables are selected to mitigate renal toxicity. In certain embodiments, such variable are selected to mitigate decrease in aPTT. In certain such embodiments, doses increase over time.

In certain embodiments, doses, dose frequency, and duration of the maintenance phase may be adjusted from time to time to achieve a desired effect. In certain embodiments, subjects are monitored for effects (therapeutic and/or toxic effects) and doses, dose frequency, and/or duration of the maintenance phase may be adjusted based on the results of such monitoring.

Certain Combination Therapies

In certain embodiments, one or more pharmaceutical compositions described herein are co-administered with one or more other pharmaceutical compositions. In certain embodiments, such one or more other pharmaceutical compositions are designed to treat the same disease, disorder, or condition as the one or more pharmaceutical compositions described herein. In certain embodiments, such one or more other pharmaceutical compositions are designed to treat a different disease, disorder, or condition as the one or more pharmaceutical compositions described herein. In certain embodiments, such one or more other pharmaceutical compositions are designed to treat an undesired side effect of one or more pharmaceutical compositions described herein. In certain embodiments, one or more pharmaceutical compositions described herein are co-administered with another pharmaceutical composition to treat an undesired effect of that other pharmaceutical composition. In certain embodiments, one or more pharmaceutical compositions described herein are co-administered with another pharmaceutical composition to produce a combinational effect. In certain embodiments, one or more pharmaceutical compositions described herein are co-administered with another pharmaceutical composition to produce a synergistic effect. In certain embodiments, the pharmaceutical composition as described herein comprises an antisense oligonucleotide. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 6. In certain embodiments, the antisense oligonucleotide is ISIS 416852.

In certain embodiments, one or more pharmaceutical compositions described herein and one or more other pharmaceutical compositions are administered at the same time. In certain embodiments, one or more pharmaceutical compositions described herein and one or more other pharmaceutical compositions are administered at different times. In certain embodiments, one or more pharmaceutical compositions described herein and one or more other pharmaceutical compositions are prepared together in a single formulation. In certain embodiments, one or more pharmaceutical compositions described herein and one or more other pharmaceutical

compositions are prepared separately.

In certain embodiments, pharmaceutical compositions that may be co-administered with a pharmaceutical composition described herein include anticoagulant or antiplatelet agents. In certain embodiments, pharmaceutical compositions that may be co-administered with a pharmaceutical composition described herein include NSAID/Cyclooxygenase inhibitors, such as, aspirin. In certain embodiments, pharmaceutical compositions that may be co-administered with a pharmaceutical composition described herein include adenosine diphosphate (ADP) receptor inhibitors, such as, clopidogrel (PLAVIX) and ticlopidine (TICLID). In certain embodiments, pharmaceutical compositions that may be co-administered with a pharmaceutical composition described herein include phosphodiesterase inhibitors, such as, cilostazol

(PLETAL). In certain embodiments, pharmaceutical compositions that may be co-administered with a pharmaceutical composition described herein include, glycoprotein IIB/IIIA inhibitors, such as, abciximab (REOPRO), eptifibatide (INTEGRILIN), tirofiban (AGGRASTAT), and defibrotide. In certain embodiments, pharmaceutical compositions that may be co-administered with a pharmaceutical composition described herein include, adenosine reuptake inhibitors, such as, to dipyridamole (PERSANTINE). In certain embodiments, pharmaceutical compositions that may be co-administered with a pharmaceutical composition described herein include, but are not limited to, warfarin (and related coumarins), heparin, direct thrombin inhibitors (such as lepirudin, bivalirudin), apixaban, LOVENOX (enoxaparin), and small molecular compounds that interfere directly with the enzymatic action of particular coagulation factors (e.g. rivaroxaban, which interferes with Factor Xa). In certain embodiments, the anticoagulant or antiplatelet agent is administered prior to administration of a pharmaceutical composition described herein. In certain embodiments, the anticoagulant or antiplatelet agent is administered following administration of a pharmaceutical composition described herein. In certain embodiments the anticoagulant or antiplatelet agent is administered at the same time as a pharmaceutical composition described herein. In certain embodiments, the dose of a co-administered

anticoagulant or antiplatelet agent is the same as the dose that would be administered if the anticoagulant or antiplatelet agent was administered alone. In certain embodiments the dose of a co-administered anticoagulant or antiplatelet agent is lower than the dose that would be administered if the anticoagulant or antiplatelet agent was administered alone. In certain embodiments the dose of a co-administered anticoagulant or antiplatelet agent is greater than the dose that would be administered if the anticoagulant or antiplatelet agent was administered alone.

In certain embodiments, pharmaceutical compositions that may be co-administered with a pharmaceutical composition described herein include anti-inflammatory agents. In certain embodiments, pharmaceutical compositions that may be co- administered with a pharmaceutical composition described herein include non-steroidal anti-inflammatory drugs (NSAIDS) as well as disease modifying drugs. "NSAIDS" reduce inflammatory reactions in a subject but in general do not ameliorate or prevent a disease from occurring or progressing. NSAIDS include, but are not limited to, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen,

indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam and tramadol. "Disease modifying drug" refers to any agent that modifies the symptoms and/or progression associated with an inflammatory disease, disorder or condition, including

autoimmune diseases (e.g. arthritis, colitis or diabetes), trauma or surgery-related disorders, sepsis, allergic inflammation and asthma. DMARDs modify one or more of the symptoms and/or disease progression associated with these diseases, disorders or conditions. Examples of disease modifying drugs include, but are not limited to, methotrexate, abatacept, infliximab,

cyclophosphamide, azathioprine, corticosteroids, cyclosporin A, aminosalicylates, sulfasalazine, hydroxychloroquine, leflunomide, etanercept, efalizumab, 6-mercapto-purine (6-MP), and tumor necrosis factor-alpha (TNFalpha) or other cytokine blockers or antagonists. The compound of the invention and one or more disease modifying drug can be administered concomitantly or sequentially. In certain embodiments, the anti -inflammatory agent is administered prior to administration of a pharmaceutical composition described herein. In certain embodiments, the anti-inflammatory agent is administered following administration of a pharmaceutical composition described herein. In certain embodiments the anti-inflammatory agent is administered at the same time as a pharmaceutical composition described herein. In certain embodiments, the dose of a co-administered anti-inflammatory agent is the same as the dose that would be administered if the anti-inflammatory agent was administered alone. In certain embodiments the dose of a co-administered anti-inflammatory agent is lower than the dose that would be administered if the anti-inflammatory agent was administered alone. In certain embodiments the dose of a co-administered anti-inflammatory agent is greater than the dose that would be administered if the anticoagulant or antiplatelet agent was administered alone.

In certain embodiments, the co-administration of a second pharmaceutical composition enhances the anticoagulant or anti-inflammatory effect of a pharmaceutical composition described herein, such that co-administration of the two pharmaceutical compositions results in an anticoagulant or anti-inflammatory effect that is greater than the effect of administering the pharmaceutical composition described herein. In certain embodiments, the co-administration results in anticoagulant or anti-inflammatory effects that are additive of the effects of the compositions when administered alone. In certain embodiments, the co-administration results in anticoagulant or anti-inflammatory effects that are supra-additive of the effects of the compositions when administered alone. In certain embodiments, the co-administration of a second composition increases antithrombotic activity or anti-inflammatory activity without increased bleeding risk. In certain embodiments, the pharmaceutical composition described herein, or the first pharmaceutical composition, is an antisense compound. In certain

embodiments, the second pharmaceutical composition is an antisense compound.

Certain Co-Administered Antiplatelet Therapies

In certain embodiments, pharmaceutical compositions described herein are combined with antiplatelet therapies. In certain embodiments, administration of a pharmaceutical composition described herein in combination with an antiplatelet therapy results in little to no appreciable or detectable increase in risk of bleeding as compared to antiplatelet therapy alone. In certain embodiments, the risk profile or risk indications are unchanged over antiplatelet therapy alone. In certain embodiments, the pharmaceutical composition described herein is an antisense oligonucleotide. The combination of antiplatelet and anticoagulant therapy is used in clinical practice most frequently in patients diagnosed with, for example, thromboembolism, atrial fibrillation, a heart valve disorder, valvular heart disease, stroke, coronary artery disease (CAD), and in patients having a mechanical valve. The benefit of dual therapy relates to the probable additive effect of suppressing both platelet and coagulation factor activities. The risk of dual therapy is the potential for increased bleeding (Dowd, M. Plenary Sessions/Thrombosis Research 123 (2008)).

Prior combinations of antiplatelet and anticoagulant therapy have been shown to increase the risk of bleeding compared with anticoagulant or antiplatelet therapy alone. Such combinations include, FXa inhibitors (e.g., apixiban and rivaroxaban) with ADP receptor/P2Y12 inhibitors (Thienopyridines such as clopidogrel - also known as PLAVIX) and NSAIDs (e.g., aspirin and naproxen) (Kubitza, D. et al., Br. J. Clin. Pharmacol. 63:4 (2006); Wong, P.C. et al. Journal of Thrombosis and Haemostasis 6 (2008); FDA Advisory Committee Briefing

Document for New Drug Application 22-406 (2009)). For example, Wong reports that addition of certain doses of apixaban to aspirin and to aspirin plus clopidogrel produced a significant increase in bleeding time compared with aspirin alone and aspirin plus clopidogrel. Kubitza reports that the combination administration of rivaroxaban and naproxen significantly increased bleeding time over naproxen alone. Certain Indications

In certain embodiments, described herein are methods of treating a subject comprising administering one or more pharmaceutical compositions described herein. In certain

embodiments, such subject has a thromboembolic condition. In certain embodiments, a thromboembolic conditions means any disease, disorder, or condition involving an embolism caused by a thrombus. In certain embodiments, examples of such diseases, disorders, and conditions include, but are not limited to, thrombosis, embolism, thromboembolism, infarct, deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and coronary artery disease (CAD). In certain embodiments, such subject has been identified as at risk for developing a thromboemoblic condition. In certain embodiments, such subjects are at risk of developing a thromboembolic conditions due to various genetic, situational, disease, or environmental factors. In certain embodiments, such factors may include, but are not limited to, surgery, cancer, malignancy, pregnancy, older age, use of oral contraceptives, immobility, sepsis, having a mechanical heart valve, valvular heart disease, atrial fibrillation, atherosclerosis atrial fibrillation, genetic predisposition, antiphospholipid syndrome, and inherited or acquired prothrombotic clotting disorders, such as Factor V Leiden. Identifying a subject at risk for developing a thromboembolic condition may be accomplished by any method including evaluating a subject's medical history and standard clinical tests or assessments. In certain embodiments, the subject has been identified as in need of anticoagulation therapy. Examples of such subjects include, but are not limited to, those undergoing major orthopedic surgery (e.g., hip/knee replacement or hip fracture surgery) and patients in need of chronic treatment, such as those suffering from arterial fibrillation to prevent stroke. In certain embodiments the invention provides methods for prophylactically reducing Factor XI mRNA or protein expression in a subject. Certain embodiments include treating a subject in need thereof by administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI.

embodiments, such subject has an inflammatory condition. In certain embodiments, an inflammatory condition means any disease, disorder or condition related to an inflammatory response to injury or stimulus characterized by clinical signs of increased redness (rubor), temperature (calor), swelling (tumor), pain (dolor) and/or loss of function (functio laesa) in a tissue. In certain embodiments, examples of such diseases, disorders, and conditions include, but are not limited to, arthritis, colitis, diabetes, sepsis, allergic inflammation, asthma,

immunoproliferative disease, antiphospholipid syndrome, graft-related disorder, trauma, autoimmune diseases, or surgery-related disorders. Examples of arthritis include, but are not limited to, rheumatoid arthritis, juvenile rheumatoid arthritis, arthritis uratica, gout, chronic polyarthritis, periarthritis humeroscapularis, cervical arthritis, lumbosacral arthritis,

osteoarthritis, psoriatic arthritis, enteropathic arthritis and ankylosing spondylitis. Examples of colitis include, but are not limited to, ulcerative colitis, Inflammatory Bowel Disease (IBD) and Crohn's Disease. Examples of graft-related disorders include, but are not limited to, graft versus host disease (GVHD), disorders associated with graft transplantation rejection, chronic rejection, and tissue or cell allografts or xenografts. Examples of immunoproliferative diseases include, but are not limited to, cancers (e.g., lung cancers) and benign hyperplasias. Examples of autoimmune diseases include, but are not limited to, lupus (e.g., lupus erythematosus, lupus nephritis), Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, diabetes (e.g. insulin dependent diabetes mellitus, type I diabetes mellitus, type II diabetes mellitus), good pasture's syndrome, myasthenia gravis, pemphigus, Crohn's disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulcerative colitis, Sjogren's syndrome, rheumatic diseases (e.g., rheumatoid arthritis), polymyositis, scleroderma, psoriasis, and mixed connective tissue disease. In certain embodiments, such subject has been identified as at risk for developing an

inflammatory condition. In certain embodiments, such subjects are at risk of developing an inflammatory condition due to various genetic, situational, disease, or environmental factors. In certain embodiments, such factors may include, but are not limited to, familial history of inflammatory disease such as diabetes, colitis or arthritis, exposure to allergens such as pollen, exposure to material such as asbestos or environmental pollutants. Identifying a subject at risk for developing an inflammatory condition may be accomplished by any method including evaluating a subject's medical history and standard clinical tests or assessments. In certain embodiments, the subject has been identified as in need of anti-inflammatory therapy. Examples of such subjects include, but are not limited to, those subject who have been diagnosed with an inflammatory condition and those subjects who have a risk factor for developing an

inflammatory condition. In certain embodiments, described herein are methods for

prophylactically reducing Factor XI mRNA or protein expression in a subject. Certain embodiments include treating a subject in need thereof by administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI.

In certain embodiments, described herein is a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI as described herein, for use in a therapeutic or prophylactic method of treating a subject that comprises administering the pharmaceutical composition as described herein. In certain embodiments, the subjet has a thromboembolic condition, the subject has been identified as at risk for developing a thromboembolic condition, or the subject has been identified as in need of anticoagulation therapy. In certain embodiments, the subject has an inflammatory condition, the subject has been identified as at risk for developing an inflammatory condition, or the subject has been identified has in need of anti-inflammatory therapy.

In certain embodiments, described herein is the use of a modified antisense

oligonucleotide complementary to a nucleic acid encoding human Factor XI as described herein in the manufacture of a pharmaceutical composition for use in a therapeutic or prophylactic method of treating a subject that comprises administering the pharmaceutical composition as described herein. In certain embodiments, the subject has a thromboembolic condition, the subject has been identified as at risk for developing a thromboembolic condition, the subject has been identified as in need of anticoagulation therapy. In certain embodiments, the subject has an inflammatory condition, the subject has been identified as at risk for developing an inflammatory condition, or the subject has been identified as in need of anti-inflammatory therapy.

In certain embodiments, administration of a therapeutically effective amount of a pharmaceutically composition as described herein is accompanied by monitoring of Factor XI mRNA expression, Factor XI protein expression, Factor XI activity, and/or Factor XI antigen in the serum of a subject, to determine the subject's response to administration of the

pharmaceutical composition. A subject's response to administration of the antisense compound is used by a physician to determine the amount and duration of therapeutic intervention.

In certain embodiments, provided herein are methods for decreasing expression of Factor XI mRNA and/or Factor XI protein in a subject. In certain embodiments, provided herein are methods for decreasing Factor XI activity and/or Factor XI antigen. In certain embodiments, Factor XI mRNA expression is decreased in a subject by 1-100%, or a range defined by any two of these values. In certain embodiments, Factor XI mRNA expression is decreased in a subject by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% ,31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%). In certain embodiments, Factor XI protein expression is decreased in a subject by 1-100%), or a range defined by any two of these values. In certain embodiments, Factor XI protein expression is decreased in a subject by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% ,31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In certain embodiments, Factor XI activity expression is decreased in a subject by 1-100%), or a range defined by any two of these values. In certain embodiments, Factor XI activity is decreased in a subject by 1%, 2%, 3%, 4%, 5%, 6%», 7%., 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%», 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% ,31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In certain embodiments, Factor XI antigen is decreased in a subject by 1-100%), or a range defined by any two of these values. In certain embodiments, Factor XI antigen is decreased in a subject by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% ,31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In certain embodiments, "decreases Factor XI activity" means a reduction in the amount of Factor XI or a marker of Factor XI measured in the serum of a subject at pre-dose versus a relevant timepoint after dosing with an antisense oligonucleotide described herein. In certain embodiments, the releveant timepoint after dosing is 1 hour, 2 hours, 3, hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after dosing. In certain embodiments, the relevant timepoint after dosing is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after dosing. In certain embodiments, the relevant timepoint after dosing is a final dose of Factor XI antisense oligonucleotide

administered to asubject or an intermediate dose of Factor XI antisense oligonucleotide administered to a subject. In certain embodiments, "decreases Factor XI antigen" means a reduction in the amount of Factor XI antigen or a marker of Factor XI antigen measured in the serum of a subject at pre-dose versus a relevant timepoint after dosing with an antisense oligonucleotide described herein. In certain embodiments, the releveant timepoint after dosing is 1 hour, 2 hours, 3, hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, or 24 hours after dosing. In certain embodiments, the relevant timepoint after dosing is 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days after dosing. In certain embodiments, the relevant timepoint after dosing is a final dose of Factor XI antisense oligonucleotide administered to asubject or an intermediate dose of Factor XI antisense oligonucleotide administered to a subject.

In certain embodiments, administration of a pharmaceutical composition as described herein results in a change in a measure of blood clotting as measured by a standard test, for example, but not limited to, activated partial thromboplastin time (aPTT) test, prothrombin time (PT) test, thrombin time (TCT), bleeding time, or D-dimer. In certain embodiments,

administration of a pharmaceutical composition as described herein increases the measure by 1 - 100%, or a range defined by any two of these values. In certain embodiments, administration of a pharmaceutical composition as described herein increases the measure by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30% ,31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In certain embodiments, administration of a pharmaceutical composition as described herein decreases the measure by 1-100%, or a range defined by any two of these values. In certain embodiments, administration of a pharmaceutical composition as described herein decreases the measure by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71 %, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%. In certain embodiments, administration of a pharmaceutical composition as described herein does not affect the measure.

In certain embodiments, the invention provides methods for decreasing Factor XI concentration in a subject while reducing side effects associated with treatment. In certain embodiments, a side effect is liver toxicity. In certain embodiments, a side effect is abnormal liver function. In certain embodiments, a side effect is liver inflammation or other adverse event that occurs in the liver. In certain embodiments, a side effect is elevated alanine

aminotransferase (ALT). In certain embodiments, a side effect is elevated aspartate

aminotransferase (AST).

In certain embodiments the methods described herein improve the cardiovascular outcome in a subject. In certain embodiments improved cardiovascular outcome is the reduction of the risk of developing a thromboembolic condition. In certain embodiments, improved cardiovascular outcome is a reduction in the occurrence of one or more major cardiovascular events, which include, but are not limited to, death, myocardial infarction, reinfarction, stroke, cardiogenic shock, pulmonary edema, cardiac arrest, and atrial dysrhythmia. In certain embodiments, the improved cardiovascular outcome is evidenced by improved carotid intimal media thickness. In certain embodiments, improved carotid intimal media thickness is a decrease in thickness. In certain such embodiments, improved carotid intimal media thickness is a prevention an increase of intimal media thickness.

Potency and Efficacy

In certain embodiments, pharmaceutical compositions comprising antisense

oligonucleotides described herein are more potent when administered parenterally than prior antisense oligonucleotides which have been administered parenterally. In certain embodiments, more potent drugs are advantageous because they have a quicker onset of action. In certain embodiments, more potent drugs are advantageous because they are more efficacious.

In certain embodiments, increased potency of the antisense oligonucleotides described herein versus prior antisense oligonucleotides facilitates the administration of a lower dose of the antisense oligonucleotides described herein to achieve a therapeutic or physiologic effect, e.g., a lower effective amount is required when administering the antisense oligonucleotides described herein versus prior antisense oligonucleotides. In certain embodiments, it is advantageous to administer a lower dose of an antisense oligonucleotide to reduce risk of potential side effects. In certain embodiments, it is advantageous to administer a lower dose of an antisense oligonucleotide to reduce cost of goods. In certain embodiments, it is advantageous to administer a lower dose of an antisense oligonucleotide to increase convenience and ease of use. In certain embodiments, it is advantageous to administer a lower dose of an antisense oligonucleotide to increase patient compliance. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 5. In certain embodiments, the antisense oligonucleotide is ISIS 416858. In certain embodiments, the antisense oligonucleotide has the nucleobase sequence of SEQ ID NO: 6. In certain embodiments, the antisense oligonucleotide is ISIS 416852.

In certain embodiments, potency can be determined by quantifying the level of target nucleic acid reduction after administration with a given amount of a pharmaceutical composition comprising an antisense oligonucleotide. In certain embodiments, decrease of target protein expression and decrease of target mRNA expression are measures of target nucleic acid reduction. In certain embodiments, decrease of target protein activity and decrease of target protein antigen are measures of target nucleic acid reduction.

In certain embodiments, relative potency between different pharmaceutical compositions can be compared by (1) quantifying the level of reduction of a first target nucleic acid after administration with a given amount of a first pharmaceutical composition comprising a first antisense oligonucleotide, (2) comparing the level of reduction of a second target nucleic acid after administration with a given amount of a second pharmaceutical composition comprising a second antisense oligonucleotide.

EXAMPLES Non-limiting disclosure and incorporation by reference

While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references recited in the present application is incorporated herein by reference in its entirety.

Example 1: Effect of ISIS 416858 targeting human Factor XI in a Phase 1, double-blind, placebo-controlled, dose-escalation study

A double-blind, placebo-controlled, dose-escalation, Phase 1 study was conducted to assess the safety, tolerability, and pharmacokinetics of single and multiple doses of ISIS 416858 administered subcutaneously to healthy volunteers.

Treatment

Healthy subjects aged 18 to 65 years were randomly assigned in a 3:1 ratio to receive ISIS 416858 (an antisense oligonucleotide having the nucleobase sequence

"ACGGCATTGGTGCACAGTTT", incorporated herein as SEQ ID NO: 5) or placebo (PBS). One day before the initiation of the study ("day 0"), levels of Factor XI antigen and activity, as well as PT and aPTT levels, were measured and these were considered pre-dose values. ISIS 416858 or PBS was administered from Day 1 onwards. The single ascending dose (SAD) cohorts of the SAD/MAD study are presented in Table 1. The subjects in the SAD cohorts received a single subcutaneous injection of PBS or ISIS 416858 at a dose of 50 mg, 100 mg, 200 mg, or 300 mg, as specified in Table 1.

The multiple ascending dose (MAD) cohorts of the SAD/MAD study are presented in Table 2. During the induction phase, the subjects in the MAD cohorts received three

subcutaneous injections of PBS or ISIS 416858 at a dose of 50 mg, 100 mg, 200 mg, or 300 mg during week 1 on alternate days (Days 1, 3, and 5), as specified in Table 2. Thus, during the induction phase, patients received a total weekly dose of 150 mg, 300 mg, 600 mg, or 900 mg. The induction phase was followed by a maintenance phase consisting of once weekly

subcutaneous administrations of ISIS 416858 at a dose of 50 mg, 100 mg, 200 mg, or 300 mg, as specified in Table 2, during weeks 2 through 6. Plasma Factor XI activity and Factor XI antigen levels were measured at regular intervals. PT and aPTT were also analyzed at regular intervals as was plasma concentration of ISIS 416858.

Table 1

Single Ascending Dose Cohorts in the SAD MAD study

Table 2

Multiple Ascending Dose Cohorts in the SAD/MAD study

Fll activity and antigen analyses Factor XI antigen levels and Factor XI activity in the plasma were analyzed using the

BCS® XP system chemistry analyzer and FXI-FSL and FXI-FS assay kits. Antigen and activity levels were measured to assess the potency of antisense inhibition of Factor XI by ISIS 416858.

The results for the SAD cohorts are presented in Tables 3-6. Tables 3 and 5 present the absolute values for Factor XI activity and antigen levels. Tables 4 and 6 present the percentage change in Factor XI activity and antigen levels for all patients compared to the pre-dose values. The results for the MAD cohorts are presented in Tables 7-10. Tables 7 and 9 present the absolute values for Factor XI activity and antigen levels. Tables 8 and 10 present the percentage change in Factor XI activity and antigen levels for all patients compared to the pre-dose values. A negative value indicates a percentage decrease in levels, whereas a positive value indicates a percentage increase in levels. Percent change after ISIS oligonucleotide treatment was compared with percent change after PBS treatment for each value using either ANOVA or Wilcoxon rank sum test to evaluate the significance of the findings. A P value of less than 0.05 for either test was considered significant and is marked with an asterisk (*). Values which had a P value of less than 0.001 are marked with a '#'. The Kolmogorov-Smirmov statistical test was used to confirm that the data for the overall study population was normally distributed.

The results indicate that both Factor XI antigen levels and Factor XI activity were significantly reduced in several cohorts. In the SAD cohorts, Factor XI activity was reduced by day 2 for the cohorts treated with 50 mg, 200 mg, and 300 mg and Factor XI antigen levels were reduced by day 4 for cohorts treated with 50 mg, 100 mg, 200 mg, and 300 mg. In the MAD cohorts, Factor XI activity was reduced by day 8 for the cohorts treated with 50 mg, 100 mg, 200 mg and 300 mg and Factor XI antigen levels were reduced by day 5 for the cohorts treated with 50 mg, 100 mg, 200 mg and 300 mg of ISIS 416858. These cohorts were unblinded, therefore, placebo subjects are pooled for measurements. Therefore, administration of Factor XI effectively reduced Factor XI antigen and Factor XI activity.

Table 3

Preliminary analysis for Factor XI activity (U/mL) in the SAD cohorts

Table 4

Preliminary analysis for percent change in Factor XI activity relative to the baseline in the SAD cohorts

Placebo PBS - 10 0 +2 +5 0

Table 5

Preliminary analysis for Factor XI antigen (U/mL) in the SAD cohorts

Table 6

Preliminary analysis for percent change in Factor XI antigen relative to the baseline in the SAD cohorts

Table 7

Preliminary analysis for Factor XI activity (U/mL) in the MAD cohorts

Table 8

Preliminary analysis for percent change in Factor XI activity relative to the baseline in the MAD cohorts

Table 9

Preliminary analysis for Factor XI antigen (U/mL) in the MAD cohorts

Table 10

Preliminary analysis for percent change in Factor XI antigen relative to the baseline in the MAD cohorts

PT and aPTT assay

Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) were measured using the BCS® XP system chemistry analyzer and a PT/aPTT assay kit. PT and aPTT values for the SAD cohorts are provided in Tables 11 -14. Tables 11 and 13 present the absolute values for PT and aPTT. Tables 12 and 14 present percent change for each value compared to pre-dose values. PT and aPTT values for the MAD cohorts are provided in Tables 15-18. Tables 15 and 17 present the absolute values for PT and aPTT. Tables 16 and 18 present percent change for each value compared to pre-dose values. A negative value indicates a percentage decrease in value, whereas a positive value indicates a percentage increase in value. Percent change after ISIS oligonucleotide treatment was compared with percent change after PBS treatment for each value using either ANOVA or Wilcoxon rank sum test to evaluate the significance of the findings. A P value of less than 0.05 for either test was considered significant and is marked with an asterisk (*). Values which had a P value of less than 0.001 are marked with a '#'. The Kolmogorov-Smirmov statistical test was used to confirm that the data for the overall study population was normally distributed. There was very little change in PT for all treatment cohorts in both the SAD and MAD groups. The aPTT values for the SAD cohorts indicate that there were no significant changes in aPTT levels after a single dose administration of 50 mg or 100 mg of ISIS 416858. There was a statistically significant increase in aPTT after a single dose administration of 200 mg and 300 mg of ISIS 416858 at day 15. In the MAD cohorts, there was a statistically significant and sustained increase in aPTT of the cohort treated with 200 mg and 300 mg of ISIS 416858. PT and aPTT were monitored as a safety precaution to mitigate the risk of bleeding after administration of the antisense oligonucleotide. To prevent potential bleeding events, in the event of a confirmed aPTT value >2 times the upper limit of normal (ULN), dosing with ISIS 416858 or placebo would be stopped permanently. Even at the highest dosing amounts, aPTT did not reach 2 times ULN. These data indicate that ISIS 416858 is tolerable for all doses tested because

administration did not cause any adverse side-effects, such as elevated aPTT, which is an indicator of bleeding. These data also suggest that antisense reduction of Factor XI affects the contact activation pathway, but not the extrinsic pathway of blood coagulation since PT was not affected whereas aPTT increased at a safe level.

Table 11

Preliminary analysis for PT (seconds) in the SAD cohorts

ISIS

D 300 6 8.75 8.47 8.73 8.57 8.77 416858

Placebo PBS - 10 8.62 8.37 8.72 8.47 8.51

Table 12

Preliminary analysis for percent change in PT relative to pre-dose in the SAD cohorts

Table 13

Preliminary analysis for aPTT (seconds) in the SAD cohorts

Table 14

Prebminary analysis for percent change in aPTT relative to pre-dose in the SAD cohorts

Table 15

Preliminary analysis for PT (seconds) in the MAD cohorts

Table 16

5 Preliminary analysis for percent change in PT relative to pre-dose in the MAD cohorts

Table 17

Preliminary analysis for aPTT (seconds) in the MAD cohorts

Table 18

Preliminary analysis for percent change in aPTT relative to pre-dose in the MAD cohorts

ISIS 416858 plasma concentration

The concentration levels of ISIS 416858 in the plasma were measured on different days of the MAD study, using a hybridization ELIS A method. The measurements were done prior to dosing (designated as 0 hr) and at several time points (hrs) after dosing, as indicated in Table 19. The data indicates that ISIS 416858 was absorbed rapidly into the systemic circulation following subcutaneous injections. After reaching C_max mean plasma concentrations of ISIS 416858 declined in a bi-phasic fasion with time, with an initial, relatively fast distribution phase that dominated the plasma clearance followed by a slower elimination phase.

Table 19

Preliminary Summary of Plasma ISIS 416858 concentrations (g/mL) in the MAD cohorts

36 12 8 0.3 ± 0.173

36 24 9 0.033 ± 0.0212

36 72 8 0.00934 ± 0.00189

36 168 8 0.00936 ± 0.00338

36 336 8 0.00736 ± 0.0022

36 672 8 0.00463 ± 0.00144

36 1008 8 0.00295 ± 0.00149

1 0 9 BLQ

1 0.5 9 0.869 ± 0.389

1 1 9 1.662 ± 0.565

1 1.5 9 2.334 1 0.729

1 2 9 3.002 ± 0.903

1 3 9 3.481 ± 1.301

1 4 9 3.439 ± 1.06

1 6 9 3.019 ± 1.054

1 8 9 1.999 ± 0.678

1 12 9 1.096 ± 0.373

1 24 9 0.0911 ± 0.063

1 48 9 0.0077 ± 0.0039

5 0 9 0.011 ± 0.0044

8 0 9 0.0101 ± 0.0036

15 0 9 0.0101 ± 0.0032

22 0 9 0.0107 ± 0.0037 mg 29 0 9 0.0116 ± 0.0033

36 0 9 0.0127 ± 0.0039

36 0.5 9 1.096 ± 0.395

36 1 9 2.237 ± 0.598

36 1.5 9 3.173 ± 1.021

36 2 9 3.851 ± 1.101

36 3 9 4.007 ± 0.94

36 4 9 4.154 ± 1.108

36 6 9 3.435 ± 0.903

36 8 9 2.232 ± 0.586

36 12 9 0.964 ± 0.825

36 24 9 0.0702 ± 0.0437

36 72 9 0.0156 ± 0.0035

36 168 9 0.0134 ± 0.0038

36 336 9 0.0106 ± 0.0038

36 672 9 0.00597 ± 0.00186

36 1008 9 0.0042 ± 0.00173 mg 1 0 9 BLQ 1 0.5 9 1.143 ± 0.514

1 1 9 2.639 1 1.235

1 1.5 9 3.815 ± 1.702

1 2 9 4.578 ± 1.708

1 3 9 5.5 ± 1.959

1 4 9 5.757 ± 1.939

1 6 9 5.635 ± 2.111

1 8 9 3.96 ± 1.248

1 12 9 2.644 ± 0.909

1 24 9 0.344 ± 0.288

1 48 9 0.0141 ± 0.009

5 0 9 0.0248 ± 0.0132

8 0 9 0.023 ± 0.0072

15 0 9 0.0227 ± 0.0061

22 0 9 0.0237 ± 0.0071

29 0 9 0.0272 ± 0.0069

36 0 9 0.0295 ± 0.0081

36 0.5 9 1.193 ± 0.568

36 1 9 3.093 ± 1.115

36 1.5 9 4.521 ± 1.596

36 2 9 5.512 ± 1.436

36 3 9 6.62 ± 1.915

36 4 9 7.029 ± 2.202

36 6 9 6.072 ± 1.88

36 8 9 4.722 ± 1.915

36 12 9 2.63 ± 0.988

36 24 9 0.29 ± 0.265

36 72 9 0.0389 ± 0.0133

36 168 9 0.0303 ± 0.0087

36 336 9 0.0224 ± 0.0089

36 672 8 0.0126 ± 0.0045

36 1008 9 0.00949 ± 0.0033

Data presented are mean ± standard deviation (SD).

N= number of observations

BLQ= below the lower limit of quantitation (LLOQ = 0.002 LglmL·) Example 2: Predictive clinical pharmacokinetic/ pharmacodynamic model of ISIS 416858

The mean pharmacokinetic (PK) and pharmacodynamic (PD) data of ISIS 416858 obtained from the Phase 1 clinical trial described above were used for sequential modeling (PK model followed by a PK/PD model). From the developed PK/PD model, simulated Factor XI activity-time profiles for various dosing regimens were generated using the mean ISIS 416858 concentration-time data and Factor XI activity-time data of Example 1.

The modeling was done sequentially with PK modeling performed first, using

WinNonlin^® 5.3 software (Pharsight Corporation), followed by PK/PD modeling, using

NONMEM^® 7.2 software (GloboMax LLC) and PDx-Pop Version 5.0 (GloboMax LLC). Plots were prepared using Tibco Spotfire SPLUS Version 8.1 (Tibco Software, Inc.).

PK model

The parameters for this model were derived by non-linear regression, in which the concentration versus time data from each separate dose cohort was modeled by a mathematical function (equation). The data was fitted by a method of successive approximations until the best fit values for the model parameters were obtained. These best fit parameters were based on a goodness of fit statistic and were reported by the software.

PK/PD model

The estimated PK parameters were incorporated into a PK/PD modeling dataset. The data of the observed mean Factor XI activity [as a percentage of the baseline value at different time points from selected single dose (100 mg, 200 mg, and 300 mg) and multiple dose (100 mg and 200 mg) cohorts] versus time profiles were fitted using NONMEM^® 7.2 software by applying an indirect response model (inhibition of Factor XI activity by ISIS 416858).

Based on the data, PD parameter estimates from the developed PK/PD model were generated. Based on the modeling and the actual data evaluated, a reasonable fit of the population PD data was obtained, as shown in Figures 2 and 3.

Simulations

Using the developed PK/PD model, various dose regimens were simulated and are presented in Figures 4 and 5. In general, the model indicates that ISIS 416858 'total dose' regimens of 300 mg or more per month will generate steady-state FXI activity that is at or below 50% of the pre-dose Fl 1 activity.

As shown in Figure 4, the simulations predict, based on phase I clinical data provided in Example 1 , that a dose of: • 200 mg of ISIS 416858 administered once bi-weekly will reduce Factor XI activity by approximately 55-65%;

• 200 mg of ISIS 416858 administered once weekly will reduce Factor XI activity by approximately 70-80%;

• 200 mg of ISIS 416858 administered once monthly will reduce Factor XI activity by approximately 35-45%;

• 400 mg of ISIS 416858 administered once bi-weekly will reduce Factor XI activity by approximately 70-80%;

• 400 mg of ISIS 416858 administered once monthly will reduce Factor XI activity by approximately 50-60%;

• 600 mg of ISIS 416858 administered once monthly will reduce Factor XI activity by approximately 60-70%; and

• 600 mg of ISIS 416858 administered once every other month will reduce Factor XI activity by approximately 30-50%.

As shown in Figure 5, the simulations predict, based on phase I clinical data provided in Example 1 , that doses of

• 100 mg of ISIS 416858 administered once weekly will reduce Factor XI activity by approximately 55-65%;

• 150 mg of ISIS 416858 administered once weekly will reduce Factor XI activity by approximately 65-75%;

• 150 mg of ISIS 416858 administered once bi-weekly will reduce Factor XI activity by approximately 45-55%;

• 300 mg of ISIS 416858 administered once bi-weekly will reduce Factor XI activity by approximately 65-75%.

• 300 mg of ISIS 416858 administered once monthly will reduce Factor XI activity by approximately 45-55%; and

• 500 mg of ISIS 416858 administered once monthly will reduce Factor XI activity by approximately 55-65%

Therefore, treatment with ISIS 416858 results in a very potent reduction of Factor XI, which is an unexpected property of this antisense oligonucleotide. Effects achieved with ISIS 416858 are different than other antisense oligonucleotides tested with similar chemical modifications. ISIS 416858 can achieve greater affects at lower doses than prior antisense oligonucleotides. Based on the phase I clinical data, as well as predictive simulations, various dosing regimens of ISIS 416858 can achieve potent reduction of target mRNA and target protein expression as measured by decrease in activity and antigen level.

Example 3: Prevention of venous thromboembolism in patients undergoing total knee arthroplasty (TKA) by treatment with antisense oligonucleotide

In a Phase 2 clinical study, patients undergoing total knee arthroplasty (TKA) are treated with l OOmg, 200mg, or 300mg of ISIS 416858 to assess the safety and efficacy of multiple doses of ISIS 416858 administered subcutaneously as compared to patients treated with enoxaparin. Patients are divided into 3 cohorts (A, B, and C) and are administered either ISIS 416858 or enoxaparin as described below in Table 20.

Table 20

Cohorts in Phase 2 Clinical Study Comparing Safety and Efficacy of

Patients treated with ISIS 416858 are administered subcutaneously once daily on days 1 , 3, 5, 8, 15, and day 23, where surgery is performed on day 22. Patients treated with enoxaparin are administered subcutaneously with 40mg enoxaparin the evening prior to surgery, 6-8 hours after surgery (i.e., 6-8 hours after wound closure), and each day for at least 8 additional days post surgery. See figure 6.

Patients will undergo a bilateral venography prior to discharge 10 ± 2 days post-surgery followed by a 12 week post treatment evaluation period. If clinical symptoms suggest pulmonary embolism (PE), objective diagnostic testing is required, i.e., a ventilation-perfusion scintigraphy, spiral CT, or pulmonary angiography, depending on local study center preference. If clinical symptoms suggest deep vein thrombosis (DVT), objective diagnostic testing is required, i.e., compression ultrasonography or venography. A clinical assessment of patients, including adverse events, symptoms, and signs of DVT or PE and bleeding events will be undertaken after TKE surgery and during the follow-up period.

The safety and tolerability of ISIS 416858 and enoxaparin is assessed by determining the incidence and severity of adverse effects (including bleeding events) and changes in laboratory evaluations including ALT and AST elevations. The primary safety outcome is the combination of major bleeding and clinical relevant non-major bleeding during treatment and up to 4 weeks after mandatory venography is completed. The secondary safety outcome is the incidence of patients with major bleeding, clinically relevant non-major bleeding, and any bleeding (including minor bleeding events) during the treatment and follow up periods (up to 120 days). Other safety parameters including adverse events, deaths, vital signs, ECG, and laboratory parameters are also recorded.

The primary efficacy outcome is the composite of asymptomatic DVT, detected by bilateral venography, and objectively confirmed symptomatic VTE, fatal PE, and unexplained death up to 12 days in the post-surgery treatment period. The secondary efficacy outcomes are all DVTs, including proximal DVTs, distal-only DVTs, and non-fatal PEs from first study drug administration up to 4 weeks after bilateral venography is performed.

Pharmacokinetic evaluations are assessed in patients treated with ISIS 416858 by measuring plasma trough and post treatment concentrations of ISIS 416858. Pharmacodynamic evaluations are assessed in patients treated with ISIS 416858 by measuring coagulation parameters such as FXI antigen and activity, aPTT, PT, and INR, which will be monitored throughout treatment and follow-up visits.

ISIS 416858 demonstrates significant FXI activity reduction with aPTT prolongation and an onset of action within 2-3 weeks without any bleeding. ISIS 416858 has an improved safety and efficacy profile as compared to standard of care treatment, such as enoxaparin, when administered to patients undergoing TKA.

Example 4: Coadministration of ISIS 416858 and enoxaparin in healthy subjects

In a Phase 1 clinical study, healthy male subjects were treated with 200mg of ISIS

416858 in combination with 40mg enoxaparin (LOVENOX) to assess safety and tolerability. On days 1, 8, and 36 subjects were treated with a single 40mg dose of enoxaparin administered subcutaneously. On days 8, 10, 12, 15, 22, and 29 subjects were treated with a single 200mg dose of ISIS 416858 administered subcutaneously. On day 8, subjects were coadministered with ISIS 416858 and enoxaparin. See Figure 7. Safety and tolerability of coadministering ISIS 416858 and enoxaparin was monitored throughout the study by assessing incidence and severity of adverse events, such as bleeding. No serious adverse events were observed. Bleeding risk was not increased in subjects treated with ISIS 416858 and enoxaparin.

Claims

What is claimed is:

1. A method of administering to a subject a single dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the single dose comprises an amount of the oligonucleotide in the range of 50-1200 mg.

2. A method of administering to a subject a single dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the single dose comprises an amount of the oligonucleotide in the range of 40- 1440 mg.

3. A method of administering to a subject a single dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the single dose comprises an amount of the oligonucleotide in the range of about 50-1200 mg.

4. The method of claim 1 , wherein the single dose is an amount of any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg.

5. The method of claim 1, wherein the single dose is an amount of any of 40-60 mg, 80-120 mg, 120-180 mg, 160-240 mg, 200-300 mg, 240-360 mg, 280-420 mg, 320-480 mg, 360-540 mg, 400-600 mg, 440-660 mg, 480-720 mg, 520-780 mg, 560-840 mg, 600-900 mg, 640-960 mg, 680-1020 mg, 720-1080 mg, 760-1 140 mg, 800-1200 mg, 840-1260 mg, 880-1320 mg, 920- 1380 mg, or 960-1440mg.

6. The method of claim 1, wherein the single dose is an amount of any of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1 100 mg, about 1150 mg, or about 1200 mg.

7. The method of claims 1-6, wherein the administering decreases Factor XI activity.

8. The method of claims 1-7, wherein the administering decreases Factor XI antigen.

9. The method of claims 1 -8, wherein the administering does not affect PT.

10. The method of claims 1 -9, wherein the administering increases aPTT.

1 1. The method of claims 1 -9, wherein the administering does not increase aPTT more than 2 times the upper limit of normal.

12. A method of administering to a subject a weekly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the weekly dose comprises an amount of the oligonucleotide in the range of 50-300 mg weekly.

13. A method of administering to a subject a weekly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the weekly dose comprises an amount of the oligonucleotide in the range of 40-360 mg weekly.

14. A method of administering to a subject a weekly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the weekly dose comprises an amount of the oligonucleotide in the range of about 50-300 mg weekly.

15. The method of claim 12, wherein the weekly dose is an amount of any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg.

16. The method of claim 13, wherein the weekly dose is an amount of any of 40-60 mg, 80- 120 mg, 120-180 mg, 160-240 mg, 200-300 mg, or 240-360 mg.

17. The method of claim 14, wherein the weekly dose is an amount of any of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.

18. The method of claims 12 and 15, wherein a total weekly dose of 50 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 50 mg.

19. The method of claims 13 and 16, wherein a total weekly dose of 40-60 mg is

administered in 3 equal doses within a week, such that the total weekly dose does not exceed 40- 60 mg.

20. The method of claims 14 and 17, wherein a total weekly dose of about 50 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 50 mg.

21. The method of claims 12 and 15, wherein a total weekly dose of 100 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 100 mg.

22. The method of claims 13 and 16, wherein a total weekly dose of 80-120 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 80- 120 mg.

23. The method of claims 14 and 17, wherein a total weekly dose of about 100 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 100 mg.

24. The method of claims 12 and 15, wherein a total weekly dose of 150 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 150 mg.

25. The method of claims 13 and 16, wherein a total weekly dose of 120-180 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 120-180 mg.

26. The method of claims 14 and 17, wherein a total weekly dose of about 150 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 150 mg.

27. The method of claims 12 and 15, wherein a total weekly dose of 200 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 200 mg.

28. The method of claims 13 and 16, wherein a total weekly dose of 160-240 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 160-240 mg.

29. The method of claims 14 and 17, wherein a total weekly dose of about 200 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 200 mg.

30. The method of claims 12 and 15, wherein a total weekly dose of 250 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 250 mg.

31. The method of claims 13 and 16, wherein a total weekly dose of 200-300 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 200-300 mg.

32. The method of claims 14 and 17, wherein a total weekly dose of about 250 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 250 mg.

33. The method of claims 12 and 15, wherein a total weekly dose of 300 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 300 mg.

34. The method of claims 13 and 16, wherein a total weekly dose of 240-360 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed 240-360 mg.

35. The method of claims 14 and 17, wherein a total weekly dose of about 300 mg is administered in 3 equal doses within a week, such that the total weekly dose does not exceed about 300 mg.

36. The method of claims 12 and 15wherein a total weekly dose of 50 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 50 mg.

37. The method of claims 13 and 16, wherein a total weekly dose of 40-60 mg is

administered in 7 equal daily doses, such that the total weekly dose does not exceed 40-60 mg.

38. The method of claims 14 and 17, wherein a total weekly dose of about 50 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 50 mg.

39. The method of claims 12 and 15, wherein a total weekly dose of 100 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 100 mg.

40. The method of claims 13 and 16, wherein a total weekly dose of 80-120 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 80-120 mg.

41. The method of claims 14 and 17, wherein a total weekly dose of about 100 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 100 mg.

42. The method of claims 12 and 15, wherein a total weekly dose of 150 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 150 mg.

43. The method of claims 13 and 16, wherein a total weekly dose of 120-180 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 120-180 mg.

44. The method of claims 14 and 17, wherein a total weekly dose of about 150 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 150 mg.

45. The method of claims 12 and 15, wherein a total weekly dose of 200 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 200 mg.

46. The method of claims 13 and 16, wherein a total weekly dose of 160-240 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 160-240 mg.

47. The method of claims 14 and 17, wherein a total weekly dose of about 200 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 200 mg.

48. The method of claims 12 and 15, wherein a total weekly dose of 250 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 250 mg.

49. The method of claims 13 and 16, wherein a total weekly dose of 200-300 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 200-300 mg.

50. The method of claims 14 and 17, wherein a total weekly dose of about 250 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 250 mg.

51. The method of claims 12 and 15, wherein a total weekly dose of 300 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 300 mg.

52. The method of claims 13 and 16, wherein a total weekly dose of 240-360 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed 240-360 mg.

53. The method of claims 14 and 17, wherein a total weekly dose of about 300 mg is administered in 7 equal daily doses, such that the total weekly dose does not exceed about 300 mg.

54. The method of claims 12-53, wherein the administering decreases Factor XI activity.

55. The method of claims 12-17, 21-23, and 39-41, wherein a weekly dose of 100 mg decreases Factor XI activity in the range of 55-65%.

56. The method of claims 12-17, 21-23, and 39-41 , wherein a weekly dose of 100 mg decreases Factor XI activity about 60%.

57. The method of claims 12-17, 24-26 and 42-44, wherein a weekly dose of 150 mg decreases Factor XI activity in the range of 65-75%.

58. The method of claims 12-17, 24-26, and 42-44, wherein a weekly dose of 150 mg decreases Factor XI activity about 70%.

59. The method of claims 12-17, 27-29, and 45-47, wherein a weekly dose of 200 mg decreases Factor XI activity in the range of 70-80%.

60. The method of claims 12-17, 27-29, and 45-47, wherein a weekly dose of 200 mg decreases Factor XI activity about 75%.

61. The method of claims 12-60, wherein the administering decreases Factor XI antigen.

62. The method of claims 12-61 , wherein the administering does not affect PT.

63. The method of claims 12-62, wherein the administering increases aPTT.

64. The method of claims 12-63, wherein the administering does not increase aPTT more than 2 times the upper limit of normal.

65. A method of administering to a subject a bi-weekly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the bi-weekly dose comprises an amount of the oligonucleotide in the range of 100-600 mg.

66. A method of administering to a subject a bi-weekly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the bi-weekly dose comprises an amount of the oligonucleotide in the range of 80-720 mg.

67. A method of administering to a subject a bi-weekly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the bi-weekly dose comprises an amount of the oligonucleotide in the range of about 100-600 mg.

67. The method of claim 65, wherein the bi-weekly dose is an amount of any of 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg.

69. The method of claim 66, wherein the bi-weekly dose is an amount of any of 80-120 mg, 120-180 mg, 160-240 mg, 200-300 mg, 240-360 mg, 280-420 mg, 320-480 mg, 360-540 mg, 400-600 mg, 440-660 mg, or 480-720 mg.

70. The method of claim 67, wherein the bi-weekly dose is an amount of any of about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg.

71. The method of claims 65-70, wherein the administering decreases Factor XI activity.

72. The method of claims 65-70, wherein the bi-weekly dose of 150 mg decreases Factor XI activity in the range of 45-55%.

73. The method of claims 65-70, wherein the bi-weekly dose of 150 mg decreases Factor XI activity about 50%.

74. The method of claims 65-70, wherein the bi-weekly dose of 200 mg decreases Factor XI activity in the range of 55-65%.

75. The method of claims 65-70, wherein the bi-weekly dose of 200 mg decreases Factor XI activity about 60%.

76. The method of claims 65-70, wherein the bi-weekly dose of 300 mg decreases Factor XI activity in the range of 65-75%.

77. The method of claims 65-70, wherein the bi-weekly dose of 300 mg decreases Factor XI activity about 70%.

78. The method of claims 65-70, wherein the bi-weekly dose of 400 mg decreases Factor XI activity in the range of 70-80%.

79. The method of claims 65-70, wherein the bi-weekly dose of 400 mg decreases Factor XI activity about 75%.

80. The method of claims 65-79, wherein the administering decreases Factor XI antigen.

81. The method of claims 65-80, wherein the administering does not affect PT.

82. The method of claims 65-81, wherein the administering increases aPTT.

83. The method of claims 65-82, wherein the administering does not increase aPTT more than 2 times the upper limit of normal.

84. A method of administering to a subject monthly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the monthly dose comprises an amount of the oligonucleotide in the range of 200- 1200 mg.

85. A method of administering to a subject monthly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the monthly dose comprises an amount of the oligonucleotide in the range of 160-1440 mg.

86. A method of administering to a subject monthly dose of a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the monthly dose comprises an amount of the oligonucleotide in the range of about 200-1200 mg.

87. The method of claim 84, wherein the monthly dose is an amount of any of 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1 100 mg, 1 150 mg, or 1200 mg.

88. The method of claim 85, wherein the monthly dose is an amount of any of 160-240 mg, 200-300 mg, 240-360 mg, 280-420 mg, 320-480 mg, 360-540 mg, 400-600 mg, 440-660 mg, 480-720 mg, 520-780 mg, 560-840 mg, 600-900 mg, 640-960 mg, 680-1020 mg, 720-1080 mg, 760-1140 mg, 800-1200 mg, 840-1260 mg, 880-1320 mg, 920-1380 mg, or 960-1440 mg.

89. The method of claim 86, wherein the monthly dose is an amount of any of about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1 100 mg, about 1 150 mg, or about 1200 mg.

90. The method of claims 84-89, wherein the administering decreases Factor XI activity.

91. The method of claims 84-89, wherein the monthly dose of 200 mg decreases Factor XI activity in the range of 35-45%.

92. The method of claims 84-89, wherein the monthly dose of 200 mg decreases Factor XI activity about 40%.

93. The method of claims 84-89, wherein the monthly dose of 300 mg decreases Factor XI activity in the range of 45-55%.

94. The method of claims 84-89, wherein the monthly dose of 300 mg decreases Factor XI activity about 50%.

95. The method of claims 84-89, wherein the monthly dose of 400 mg decreases Factor XI activity in the range of 50-60%.

96. The method of claims 84-89, wherein the monthly dose of 400 mg decreases Factor XI activity about 55%.

97. The method of claims 84-89, wherein the monthly dose of 500 mg decreases Factor XI activity in the range of 55-65%.

98. The method of claims 84-89, wherein the monthly dose of 500 mg decreases Factor XI activity about 60%.

99. The method of claims 84-89, wherein the monthly dose of 600 mg decreases Factor XI activity in the range of 60-70%.

100. The method of claims 84-89, wherein the monthly dose of 600 mg decreases Factor XI activity about 65%.

101. The method of claims 84-100, wherein the administering decreases Factor XI antigen.

102. The method of claims 84-101, wherein the administering does not affect PT.

103. The method of claims 84- 102, wherein the administering increases aPTT.

104. The method of claims 84-103, wherein the administering does not increase aPTT more than 2 times the upper limit of normal.

105. A method of administering to a subject a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the administering comprises: an induction phase, wherein a dose comprising an amount of the oligonucleotide in the range of 50-1200 mg weekly for 1-15 weeks, and a maintenance phase, wherein a dose comprising an amount of the oligonucleotide in the range of 50-300 mg weekly for at least 1 week.

106. A method of administering to a subject a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the administering comprises: an induction phase, wherein a dose comprising an amount of the oligonucleotide in the range of 40-1440 mg weekly for 1-15 weeks, and a maintenance phase, wherein a dose comprising an amount of the oligonucleotide in the range of 40-360 mg weekly for at least 1 week.

107. A method of administering to a subject a pharmaceutical composition comprising a modified antisense oligonucleotide complementary to a nucleic acid encoding human Factor XI, wherein the administering comprises: an induction phase, wherein a dose comprising an amount of the oligonucleotide in the range of about 50-1200 mg weekly for 1-15 weeks, and a maintenance phase, wherein a dose comprising an amount of the oligonucleotide in the range of about 50-300 mg weekly for at least 1 week.

108. The method of claim 105, wherein a total weekly induction phase dose in an amount in the range of 50-1200 mg is administered in 7 equal daily administrations, such that the total weekly induction phase dose does not exceed 50-1200 mg.

109. The method of claim 106, wherein a total weekly induction phase dose in an amount in the range of 40-1440 mg is administered in 7 equal daily administrations, such that the total weekly induction phase dose does not exceed 40-1440 mg.

1 10. The method of claim 107, wherein a total weekly induction phase dose in an amount in the range of about 50-1200 mg is administered in 7 equal daily administrations, such that the total weekly induction phase dose does not exceed about 50-1200 mg.

1 1 1. The method of claims 105 and 108, wherein a total weekly maintenance phase dose in an amount in the range of 50-300 mg is administered in 7 equal daily administrations, such that the total weekly maintenance phase dose does not exceed 50-300 mg.

112. The method of claims 106 and 109, wherein a total weekly maintenance phase dose in an amount in the range of 40-360 mg is administered in 7 equal daily administrations, such that the total weekly maintenance phase dose does not exceed 40-360 mg.

1 13. The method of claims 107 and 110, wherein a total weekly maintenance phase dose in an amount in the range of about 50-300 mg is administered in 7 equal daily administrations, such that the total weekly maintenance phase dose does not exceed about 50-300 mg.

1 14. The method of claims 105 and 108, wherein the dose administered during the induction phase is an amount of any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, or 1200 mg administered once weekly.

115. The method of claims 106 and 109, wherein the dose administered during the induction phase is an amount of any of 40-60 mg, 80-120 mg, 120-180 mg, 160-240 mg, 200-300 mg, 240- 360 mg, 280-420 mg, 320-480 mg, 360-540 mg, 400-600 mg, 440-660 mg, 480-720 mg, 520- 780 mg, 560-840 mg, 600-900 mg, 640-960 mg, 680-1020 mg, 720-1080 mg, 760-1140 mg, 800-1200 mg, 840-1260 mg, 880-1320 mg, 920-1380 mg, or 960-1440 mg administered once weekly.

1 16. The method of claims 107 and 110, wherein the dose administered during the induction phase is an amount of any of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, or about 1200 mg administered once weekly.

1 17. The method of claim 105-110 and 114, wherein the dose administered during the maintenance phase is an amount of any of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, or 300 mg administered once weekly.

1 18. The method of claim 105- 1 10 and 1 15, wherein the dose administered during the maintenance phase is an amount of any of 40-60 mg, 80-120 mg, 120-180 mg, 160-240 mg, 200- 300 mg, or 240-360 mg administered once weekly.

119. The method of claim 105-110 and 116, wherein the dose administered during the maintenance phase is an amount of any of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg administered once weekly.

120 The method of claims 105-1 19, wherein the induction phase is one week.

121. The method of claim 120, wherein the total weekly induction phase dose is divided equally into 3 separate doses administered on separate days.

122. The method of claim 120, wherein the total weekly maintenance phase dose is divided equally into 3 separate doses administered on separate days.

123. The method of claims 105-122, wherein the administering decreases Factor XI activity.

124. The method of claims 105-123, wherein the administering decreases Factor XI antigen.

125. The method of claims 105-124, wherein the administering does not affect PT.

126. The method of claims 105-125, wherein the administering increases aPTT.

127. The method of claims 105-126, wherein the administering does not increase aPTT more than 2 times the upper limit of normal.

128. The method of any preceding claim, wherein the nucleic acid encoding human Factor XI is any of SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

129. The method of any preceding claim, wherein the modified antisense oligonucleotide is a single-stranded modified oligonucleotide.

130. The method of any preceding claim, wherein at least one internucleoside linkage of the modified antisense oligonucleotide is a modified internucleoside linkage.

131. The method of claim 130, wherein at least one internucleoside linkage is a phosphorothioate internucleoside linkage.

132. The method of claim 131 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

133. The method of any preceding claim, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified sugar.

134. The method of claim 133, wherein at least one modified sugar is a bicyclic sugar.

135. The method of claim 134, wherein each of the at least one bicyclic sugar comprises a 4'- (CH₂)_n-0-2' bridge, wherein n is 1 or 2.

136. The method of claim 135, wherein each of the at least one bicyclic sugar comprises a 4'- CH(CH₃)-0-2' bridge.

137. The method of claims 133, wherein at least one modified sugar comprises a 2'-0- methoxyethyl moiety.

138. The method of any preceding claim, wherein at least one nucleoside of the modified antisense oligonucleotide comprises at least one tetrahydropyran modified nucleoside wherein a tetrahydropyran ring replaces the furanose ring.

139. The method of claim 131, wherein each of the at least one tetrahydropyran modified nucleoside has the structure:

wherein Rx is an optionally protected heterocyclic base moiety.

140. The method of any preceding claim, wherein at least one nucleoside of the modified antisense oligonucleotide comprises a modified nucleobase.

141. The method of claim 140, wherein the modified nucleobase is a 5-methylcytosine.

142. The method of claim 141 , wherein each cytosine is a 5-methylcytosine.

143. The method of any preceding claim, wherein the modified antisense oligonucleotide comprises: a gap segment consisting of linked deoxynucleosides; a 5' wing segment consisting of linked nucleosides; a 3' wing segment consisting of linked nucleosides; wherein the gap segment is positioned immediately adjacent to and between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar.

144. The method of any preceding claim, wherein the modified oligonucleotide comprises: a gap segment consisting of ten linked deoxynucleosides; a 5' wing segment consisting of five linked nucleosides; a 3' wing segment consisting of five linked nucleosides; wherein the gap segment is positioned immediately adjacent and between the 5' wing segment and the 3' wing segment, wherein each nucleoside of each wing segment comprises a 2'-0-methoxyethyl sugar; and wherein each internucleoside linkage is a phosphorothioate linkage.

145. The method of any preceding claim, wherein the modified oligonucleotide consists of 20 linked nucleosides.

146. The method of any preceding claim, wherein the nucleobase sequence of the modified antisense oligonucleotide is 100% complementary to a nucleobase sequence of SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, or SEQ ID NO: 4.

147. The method of any preceding claim, wherein the modified antisense oligonucleotide comprises the nucleobase sequence of SEQ ID NO: 5.

148. The method of any preceding claim, wherein the modified antisense oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 5.

149. The method of any preceding claim, wherein the modified antisense oligonucleotide is ISIS 416858.

150. The method of claims 1 - 146, wherein the modified antisense oligonucleotide comprises the nucleobase sequence of SEQ ID NO: 6.

151. The method of claims 1 - 146 and 151 , wherein the modified antisense oligonucleotide consists of the nucleobase sequence of SEQ ID NO: 6.

152. The method of claims 1 - 146 and 150- 151, wherein the modified antisense

oligonucleotide is ISIS 41 852.

153. The method of any preceding claim, wherein the administering decreases risk of developing a thromboembolic condition in the subject.

154. The method of any preceding claim, wherein the administering treats a thromboembolic condition in the subject.

155. The method of claims 153-154, wherein the thromboembolic disorder is any of infarct, thrombosis, embolism, thromboembolism, deep vein thrombosis, pulmonary embolism, myocardial infarction, and stroke, thrombosis, embolism, thromboembolism, and coronary artery disease (CAD).

156. The method of any preceding claim, wherein the subject is at risk for developing a thromboembolic disorder due to a risk factor.

157. The method of claim 156, wherein the risk factor is any of surgery, cancer, malignancy, pregnancy, older age, use of oral contraceptives, immobility, sepsis, having a mechanical heart valve, valvular heart disease, atrial fibrillation, atherosclerosis atrial fibrillation, genetic predisposition, antiphospholipid syndrome, inherited or acquired prothrombotic clotting disorders, and Factor V Leiden.

158. The method of claim 157, wherein the surgery is orthopedic surgery.

159. The method of claim 158, wherein the orthopedic surgery is any of hip replacement surgery, knee replacement surgery, hip fracture surgery, leg fracture surgery, arm fracture surgery, and cranial fracture surgery.

160. The method of claim 157, wherein the surgery is cosmetic surgery.

161. The method of any preceding claim, wherein the subject has been determined to be in need of anticoagulation therapy.

162. The method of any preceding claim, wherein the administering decreases risk of developing an inflammatory condition in the subject.

163. The method of any preceding claim, wherein the administering treats an inflammatory condition in the subject.

164. The method of claims 162-163, wherein the inflammatory condition is any of arthritis, colitis, diabetes, sepsis, allergic inflammation, asthma, immunoproliferative disease,

antiphospholipid syndrome, graft-related disorder, trauma, autoimmune diseases, surgery-related disorders, rheumatoid arthritis, juvenile rheumatoid arthritis, arthritis uratica, gout, chronic polyarthritis, periarthritis humeroscapularis, cervical arthritis, lumbosacral arthritis,

osteoarthritis, psoriatic arthritis, enteropathic arthritis, ankylosing spondylitis, ulcerative colitis, Inflammatory Bowel Disease (IBD), Crohn's Disease, graft versus host disease (GVHD), disorders associated with graft transplantation rejection, chronic rejection, tissue or cell allografts or xenografts, cancers (e.g., lung cancers), benign hyperplasias, lupus erythematosus, lupus nephritis, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, diabetes, good pasture's syndrome, myasthenia gravis, pemphigus, Crohn's disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulcerative colitis, Sjogren's syndrome, rheumatic diseases, polymyositis, scleroderma, psoriasis, and mixed connective tissue disease.

165. The method of any preceding claim, wherein the subject is at risk for developing an inflammatory disorder due to a risk factor.

166. The method of claim 165, wherein the risk factor is any of arthritis, colitis, diabetes, sepsis, allergic inflammation, asthma, immunoproliferative disease, antiphospholipid syndrome, graft-related disorder, trauma, autoimmune diseases, surgery-related disorders, rheumatoid arthritis, juvenile rheumatoid arthritis, arthritis uratica, gout, chronic polyarthritis, periarthritis humeroscapularis, cervical arthritis, lumbosacral arthritis, osteoarthritis, psoriatic arthritis, enteropathic arthritis, ankylosing spondylitis, ulcerative colitis, Inflammatory Bowel Disease (IBD), Crohn's Disease, graft versus host disease (GVHD), disorders associated with graft transplantation rejection, chronic rejection, tissue or cell allografts or xenografts, cancers (e.g., lung cancers), benign hyperplasias, lupus erythematosus, lupus nephritis, Hashimoto's thyroiditis, primary myxedema, Graves' disease, pernicious anemia, autoimmune atrophic gastritis, Addison's disease, diabetes, good pasture's syndrome, myasthenia gravis, pemphigus, Crohn's disease, sympathetic ophthalmia, autoimmune uveitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenia, primary biliary cirrhosis, chronic action hepatitis, ulcerative colitis, Sjogren's syndrome, rheumatic diseases, polymyositis, scleroderma, psoriasis, and mixed connective tissue disease.

167. The method of any preceding claim, wherein the subject has been determined to be in need of anti-inflammatory therapy.

168. The method of any preceding claim, wherein the modified antisense oligonucleotide is administered parenterally.

169. The method of claim 168, wherein the parenteral administration is any of subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, intraperitoneal administration, and intracranial administration.

170. The method of claims 168-169, wherein the parenteral administration is by injection or infusion.

171. The method of any preceding claim, wherein the pharmaceutical composition is coadministered with any of aspirin, clopidogrel, dipyridamole, heparin, lepirudin, ticlopidine, warfarin, apixaban, rivaroxaban, LOVENOX, and Factor Xa inhibitor or a combination thereof.

172 The method of any preceding claim, wherein the pharmaceutical composition is coadministered with 30mg or 40mg of LOVENOX.

173 The method of claim 172 wherein bleeding risk is not increased in the subject.

174. The method of any preceding claim, wherein the pharmaceutical composition is coadministered with anti-platelet therapy.

175. The method of claim 174, wherein the anti-platelet therapy is any of ADP receptor inhibitor, NSAID, phosphodiesterase inhibitor, glycoprotein IIB/IIIA inhibitor or adenosine reuptake inhibitor or a combination thereof.

176. The method of any preceding claim, wherein the pharmaceutical composition is coadministered with any of NSAIDS, acetyl salicylic acid, choline magnesium salicylate, diflunisal, magnesium salicylate, salsalate, sodium salicylate, diclofenac, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, naproxen, nabumetone, phenylbutazone, piroxicam, sulindac, tolmetin, acetaminophen, ibuprofen, Cox-2 inhibitors, meloxicam, tramadol, methotrexate, abatacept, infliximab, cyclophosphamide, azathioprine, corticosteroids, cyclosporin A, aminosalicylates, sulfasalazine, hydroxychloroquine,

leflunomide, etanercept, efalizumab, 6-mercapto-purine (6-MP), and tumor necrosis factor-alpha (TNFalpha), cytokine blockers, and antagonists.

177. The method of any preceding claim, wherein the modified antisense oligonucleotide comprises a portion of at least 8, of at least 9, of at least 10, of at least 11, of at least 12, of at least 13, of at least 14, of at least 15, of at least 16, of at least 17, of at least 18, of at least 19, of at least 20 contiguous nucleobases complementary to an equal length portion of nucleobases 1281 to 1307 of SEQ ID NO: 1, wherein the nucleobase sequence of the modified antisense oligonucleotide is at least 90% complementary to SEQ ID NO: 1.

178. The method of claim 177, wherein the nucleobase sequence of the modified antisense oligonucleotide is at least 95% complementary to SEQ ID NO: 1.

179. The method of claim 177, wherein the nucleobase sequence of the modified antisense oligonucleotide is 100% complementary to SEQ ID NO: 1.

180. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a single dose of the pharmaceutical composition, wherein the single dose comprises an amount of the oligonucleotide in the range of 50-1200mg, in the range of 40- 1440mg, or in the range of about 50-1200mg.

181. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methyl cytosine, and each of nucleosides 1 -5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a single dose of the pharmaceutical composition, wherein the single dose comprises an amount of the oligonucleotide in the range of 50-1200mg, in the range of 40- 1440mg, or in the range of about 50-1200mg.

182. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a weekly dose of the pharmaceutical composition, wherein the weekly dose comprises an amount of the oligonucleotide in the range of 50-300 mg, in the range of 40-360 mg, or in the range of about 50-300 mg.

183. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a weekly dose of the pharmaceutical composition, wherein the weekly dose comprises an amount of the oligonucleotide in the range of 50-300 mg, in the range of 40-360 mg, or in the range of about 50-300 mg.

184. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- m ethyl cytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a bi-weekly dose of the pharmaceutical composition, wherein the biweekly dose comprises an amount of the oligonucleotide in the range of 100-600 mg, in the range of 80-720 mg, or in the range of about 100-600 mg.

185. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a bi-weekly dose of the pharmaceutical composition, wherein the biweekly dose comprises an amount of the oligonucleotide in the range of 100-600 mg, in the range of 80-720 mg, or in the range of about 100-600 mg.

186. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a monthly dose of the pharmaceutical composition, wherein the monthly dose comprises an amount of the oligonucleotide in the range of 200-1200 mg, in the range of 160-1440 mg, or in the range of about 200-1200 mg.

187. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moeity, for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject a monthly dose of the pharmaceutical composition, wherein the monthly dose comprises an amount of the oligonucleotide in the range of 200-1200 mg, in the range of 160-1440 mg, or in the range of about 200-1200 mg.

188. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence ACGGCATTGGTGCACAGTTT (SEQ ID NO:5), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moiety for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject an induction phase dose of the pharmaceutical composition, wherein the induction phase dose comprises an amount of the oligonucleotide in the range of 50-1200 mg administered weekly for 1-15 weeks, in the range of 40-1440 mg weekly for 1-15 weeks, or in the range of about 50-1200 mg weekly for 1-15 weeks; and a maintenance phase of the pharmaceutical composition, wherein the maintenance phase dose comprises an amount of the oligonucleotide in the range of 50-300 mg weekly for at least 1 week; in the range of 40-360 mg weekly for at least 1 week; or in the range of about 50-1200 mg weekly for 1 -15 weeks.

189. A pharmaceutical composition comprising a modified antisense oligonucleotide consisting of the nucleobase sequence TGGTGCACAGTTTCTGGCAG (SEQ ID NO:6), where each internucleoside linkage is a phosphorothioate internucleoside linkage, each cytosine is a 5- methylcytosine, and each of nucleosides 1-5 and 16-20 comprises a 2'-0-methoxyethyl moiety for use in a therapeutic or prophylactic method of treating a human subject that comprises administering to the subject an induction phase dose of the pharmaceutical composition, wherein the induction phase dose comprises an amount of the oligonucleotide in the range of 50-1200 mg administered weekly for 1-15 weeks, in the range of 40-1440 mg weekly for 1-15 weeks, or in the range of about 50-1200 mg weekly for 1-15 weeks; and a maintenance phase of the pharmaceutical composition, wherein the maintenance phase dose comprises an amount of the oligonucleotide in the range of 50-300 mg weekly for at least 1 week; in the range of 40-360 mg weekly for at least 1 week; or in the range of about 50-1200 mg weekly for 1-15 weeks.