Factor XI Inhibitors: Cardiovascular Perspectives

Raffaele De Caterina; Domenico Prisco; John W. Eikelboom

Disclosures

Eur Heart J. 2023;44(4):280-292.

Abstract and Introduction

Abstract

Graphical Abstract

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Possible forthcoming therapeutic indications for FXI/XIa inhibitors.

Anticoagulants are the cornerstone for prevention and treatment of thrombosis but are not completely effective, and concerns about the risk of bleeding continue to limit their uptake. Animal studies and experience from patients with genetic coagulation factor XI deficiency suggesting that this factor is more important for thrombosis than for haemostasis raises the potential for drugs that target factor XI to provide safer anticoagulation. Multiple factor XI inhibitors are currently under evaluation in clinical trials, including parenterally administered antisense oligonucleotides, monoclonal antibodies, and orally active small-molecule inhibitors. Promising results of phase 2 trials in patients undergoing major orthopaedic surgery, and in those with end-stage kidney disease, atrial fibrillation and acute coronary syndromes have led to large phase 3 trials that are currently ongoing. We here review premises for the use of these agents, results so far accrued, ongoing studies, and perspectives for future patient care.

Introduction

Heparins and vitamin K antagonists (VKAs) were the only widely available anticoagulants for more than 70 years. In the past three decades, new parenteral and oral anticoagulants have been introduced, including designer drugs that target individual coagulation proteins. The first major group of designer anticoagulants to be introduced into clinical practice were the direct oral anticoagulants (DOACs) which target either thrombin or activated coagulation factor X (FXa). To address remaining unmet needs, recent attention has focused on coagulation factor XI (FXI) as a novel target for new anticoagulants.

This review examines unmet needs related to the use of DOACs, the promise of FXI as a new therapeutic target, the pharmacological features of drugs in development that target FXI, and their possible therapeutic indications. Information included in this review is based on literature published up to 15 June 2022.

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Table 1. Properties of classes of FXI inhibitors currently in development
	ASOs	Monoclonal antibodies	Small molecules	Natural inhibitors	Aptamers
Mechanism	Block biosynthesis	Bind target protein	Bind target protein	Bind target protein	Bind target protein
Administration route	SC	IV or SC	IV or oral	IV	IV or SC
Administration frequency	Weekly to monthly	Monthly	Daily	Daily	Daily
Onset of action	Slow (weeks)	Rapid (hours to days)	Rapid (minutes to hours)	Rapid (minutes)	Rapid (minutes to hours)
Offset of action	Slow (weeks)	Slow (weeks)	Rapid (minutes to hours)	Rapid (hours)	Rapid (minutes to hours)
Renal excretion	No	No	Yes	Uncertain	No
CYP metabolism	No	No	Yes	No	No
Potential for drug–drug interactions	No	No	Yes	Unknown	No

ASO, antisense oligonucleotide; IV, intravenous; SC, subcutaneous; CYP, cytochrome P450.

Table 2. Phase 2 trials on antisense oligonucleotides targeting FXI(a)
Compound/company	Indication	Clinical trial	N. patients	Interventions	Efficacy data	Safety data
IONIS-FXI_RX/Ionis Pharmaceuticals	Post-operative (TKA)	NCT01713361	30	IONIS-FXIRX (200 mg or 300 mg, administered as three times during the first week of treatment, followed by weekly administrations) vs. enoxaparin (40 mg/day). Treatment started 36 days before surgery	Primary outcome (VTE incidence at bilateral venography/symptomatic events): 27% in the IONIS-FXIRX 200 mg group, 4% in the IONIS-FXIRX 300 mg group, 30% in enoxaparin group	Major or clinically relevant non-major bleeding events: 3% in both IONIS-FXIRX arms, 8% in enoxaparin
	ESRD requiring haemodialysis	NCT02553889	43 (49 in a first open-label phase)	IONIS-FXI_RX (200 to 300 mg, s.c.) or placebo	By Day 85, mean levels of FXI activity fell 56% in the IONIS-FXIRX 200 mg group, 71% in the 300 mg group, and 4% in placebo compared with baseline	Major bleeding events: 0–7% in IONIS-FXIRX, and 8% in placebo
	ESRD requiring haemodialysis	EMERALD trial, NCT03358030	213	IONIS-FXI_RX (200 250 or 300mg,s.c., within 2 h post-dialysis, once weekly for 26 weeks) or placebo	—	—
Fesomersen/Ionis Pharmaceuticals	ESRD requiring haemodialysis	RE-THINc ESRD trial, NCT04534114	307	IONIS-FXI-LRX (40, 80 and 120 mg s.c.) or placebo	—	—

DVT, deep vein thrombosis; ESRD, end-stage renal disease; IU, international units; i.v., intravenous; s.c, subcutaneous; TKA, total knee arthroplasty; VTE, venous thromboembolism.

Table 3. Phase 2/3 trials on monoclonal antibodies targeting FXI(a)
Compound/Company	Indication	Clinical trial	N. patients	Interventions	Efficacy data	Safety data
Osocimab/Bayer	Post-operative (TKA)	FOXTROT trial, NCT03276143	813	Pre- or post-operative doses of osocimab (0.3, 0.6, 1.2 or 1.8 mg/kg, i.v.) or enoxaparin (40 mg/day s.c.) or apixaban (2.5 mg twice daily, oral) for at least 10 days or until venography	Primary outcome (VTE incidence between 10–13 days post-operatively, assessed at bilateral venography or symptomatic events): 24% in patients on 0.3 mg/kg, 16% receiving 0.6 mg/kg, 17% receiving 1.2 mg/kg, and 18% receiving 1.8 mg/kg of osocimab post-operatively; 30% in 0.3 mg/kg and 11% in 1.8 mg/kg of osocimab pre-operatively; 26% in enoxaparin; 15% in apixaban	Major or clinically relevant non-major bleeding events: 5% in osocimab, 6% in enoxaparin, and 2% in apixaban
Osocimab/Bayer	ESRD	CONVERT, NCT04523220	686	Osocimab (105 or 210 mg single s.c. loading dose, followed by 52.5 or 105 mg monthly doses) or placebo	—	—
Abelacimab/Anthos Therapeutics	Post-operative (TKA)	ANT-005 TKA, EudraCT number 2019-003756-37	412	Abelacimab (30 mg, 75 mg, or 150 mg, single i.v. post-operative dose) or enoxaparin (40 mg/day s.c.)	VTE incidence (assessed by unilateral venography or symptomatic events): 13, 5 and 4% of patients in the 30, 75 and 150 mg abelacimab groups; 22% in enoxaparin	Major or clinically relevant non-major bleeding events: 2, 2, and 0% of patients in 30, 75 and 150 mg abelacimab; 0% in enoxaparin
	Atrial fibrillation	ANT-004, NCT04213807	18	Abelacimab (120 or 180mg, s.c. on Day 1 with two subsequent monthly injections for 3 months) or placebo	More than or equal to 50% inhibition of factor XI: 33 and 57% in abelacimab 120 and 180mg, 0% in placebo	All-cause mortality and serious adverse events: 0% in all groups
	Atrial fibrillation	AZALEA-TIMI 71, NCT04755283	1200	Abelacimab (middle or high monthly dose, s.c.) or rivaroxaban (20 mg/day orally)	—	—
	Cancer (gastrointestinal/	MAGNOLIA trial, NCT05171075	1020	Abelacimab (150 mg i.v., followed by monthly administration) or dalteparin (200 IU/kg/day followed by 150 IU/kg/day)	—	—
	genitourinary)	MAGNOLIA trial, NCT05171075	1020		—	—
	Cancer	ASTER trial, NCT05171049	1655	Abelacimab (150 mg i.v., followed by monthly administration) or apixaban (10 mg followed by 5 mg, orally twice daily)	—	—
Xisomab 3G3/Aronora	ESRD on haemodialysis	NCT03612856	24	Xisomab 3G3 (0.25 or 0.5 mg/kg, single predialysis dose) or placebo	Less occlusive events requiring haemodialysis circuit exchange, lower levels of thrombin-antithrombin complexes, C-reactive protein, potassium and iron entrapment in the dialyzers, less blood accumulation within the dialyzers.	No impaired haemostasis or other drug-related adverse events
Xisomab 3G3/Aronora	Cancer	NCT04465760	50	Xisomab 3G3 (i.v. or via catheter within 48 h of catheter placement; standard of care chemotherapy 2 days later)	—	—
MK-2060/Merck Sharp & Dohme	ESRD on haemodialysis	MK-2060-007 trial, NCT05027074	489	MK-2060 (low or high i.v. dose, every other day during week 1, then once a week after week 1) vs. placebo	—	—

DVT, deep vein thrombosis; ESRD, end-stage renal disease; IUs, international units; i.v., intravenous; s.c, subcutaneous; TKA, total knee arthroplasty; VTE, venous thromboembolism.

Table 4. Phase 2 trials on small molecules targeting FXI(a)
Compound/Company	Indication	Clinical trial	N. patients	Interventions	Efficacy data	Safety data
Milvexian/Bristol-Myers Squibb—Janssen	Post-operative (TKA)	AXIOMATIC-TKR trial, NCT03891524	1242	Seven post-operative regimens of milvexian (25, 50, 100, or 200 mg twice daily or 25, 50, or 200 mg once daily, orally) or enoxaparin (40 mg/day, s.c.)	VTE (composite of asymptomatic DVT, confirmed symptomatic VTE, or death from any cause): 21, 11, 9 and 8% in milvexian 25, 50, 100 and 200 mg twice daily; 25, 24, 7% in milvexian 25, 50, and 200 mg once daily; 21% in enoxaparin	Major or clinically relevant non-major bleeding: 1% in milvexian, 2% in enoxaparin
	ESRD requiring haemodialysis	NCT03000673	32	Different sequences of: UFH intravenous infusion; milvexian 100 mg; milvexian 300 mg; enoxaparin (40 mg by s.c. injection)	—	All-cause mortality and serious adverse events: 0% in all sequencies
	Stroke	AXIOMATIC-SSP trial, NCT03766581	2366	Milvexian (+ aspirin and clopidogrel) or placebo (+ aspirin and clopidogrel)	—	—
Asundexian/Bayer	Atrial fibrillation	PACIFIC-AF, NCT04218266	753	Asundexian (20 to 50 mg/day, once daily orally) or apixaban (5 mg twice daily)	Inhibition of FXIa activity: 90% for asundexian 20 mg at peak concentrations, 94% for asundexian 50 mg	Ratios of incidence proportions for major or clinically relevant non-major bleeding events: 0.50 (90% CI: 0.14–1.68) for asundexian 20 mg, 0.16 (0.01–0.99) for asundexian 50 mg, vs. apixaban.
	Acute heart attack	PACIFIC-AMI, NCT04304534	1592	Milvexian (low, medium or high dose, + aspirin +/- clopidogrel) or placebo (+ aspirin +/- clopidogrel)	—	—
	Stroke	PACIFIC-STROKE, NCT04304508	1808	Asundexian (low, medium or high dose, + standard antiplatelet therapy) or placebo (+ standard antiplatelet therapy)	—	—
	Renal impairment	NCT04510987	48	Asundexian (25mg, single oral dose)	—	—
EP-7041/eXIthera Pharmaceuticals	COVID-19 thromboprophylaxis	NCT05040776	90	EP-7041 (0.6 mg/kg/h i.v. or 1.0 mg/kg/h i.v. for the duration of the index hospitalization)	—	—

DVT, deep vein thrombosis; ESRD, end-stage renal disease; IUs, international units; i.v., intravenous; s.c, subcutaneous; TKA, total knee arthroplasty; VTE, venous thromboembolism.