IONIS-FXIRx / Ionis, Bayer - LARVOL DELTA

A Systematic Review of Safety and Efficacy of Factor XI/XIa Inhibitors in Patients With ESKD on Hemodialysis. (PubMed, Kidney Int Rep) - "Five phases 2 studies encompassing 1270 participants were identified, investigating gruticibart, IONIS-FXIRx, osocimab, or fesomersen in the general HD population and using placebo as a comparator. Currently available evidence does not indicate a significantly increased bleeding risk of FXI/XIa inhibitors in patients with ESKD on HD compared to placebo. Their efficacy and their association with all-cause mortality need to be investigated in sufficiently powered, randomized controlled phase 3 trials."

Journal • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease • Thrombosis

Therapeutic Potential of FXI Inhibitors: Hype or Hope? (PubMed, Drugs) - "A number of compounds with different mechanisms of action have been developed to target FXI (i.e., asundexian, abelacimab, Ionis-FXIRx, milvexian, osocimab, and Xisomab 3G). Moreover, the largest phase 3 randomized trial designed to test the efficacy of asundexian over apixaban in patients with atrial fibrillation, the OCEANIC-AF, has been prematurely stopped as a result of the inferior efficacy of asundexian. In this review we discuss the pharmacological properties and available evidence generated thus far for factor XI inhibitors, providing a perspective on the current state of these drugs."

Journal • Review • Atrial Fibrillation • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Ischemic stroke • Myocardial Infarction • Nephrology • Orthopedics • Pain • Renal Disease • Thrombosis

Safety of factor XI inhibitors in patients with end-stage kidney disease on hemodialysis: A meta-analysis of randomized controlled trials (ISTH 2024) - "We identified six RCTs assessing FXI inhibitors in patients with ESKD on hemodialysis, all using placebo as comparator. Of those, one study was still ongoing, resulting in five studies investigating FXI inhibitors (IONIS-FXIRx, xisomab, fesomersen, osocimab) encompassing 1,270 patients included in our meta-analysis (table). FXI inhibitors were associated with an OR of 0.80 (95% CI, 0.49-1.32) for the occurrence of CRB compared to placebo (Fig.)."

Retrospective data • Cardiovascular • Hematological Disorders • Nephrology • Renal Disease • Thrombosis

Drug-Drug Interactions of FXI Inhibitors: Clinical Relevance. (PubMed, Hematol Rep) - "These new inhibitors include chemical small molecules (asundexian and milvexian), monoclonal antibodies (abelacimab, osocimab, and xisomab), and antisense oligonucleotides (IONIS-FXIRX and fesomersen), and thus, they have very peculiar and different pharmacokinetic and pharmacodynamic properties. These characteristics may be useful to differentiate their use with the direct oral anticoagulant (DOAC) anti -FXa (rivaroxaban, apixaban, edoxaban) and thrombin (dabigatran), whose pharmacokinetics are strongly dependent from P-gp inhibitors/inducers. In the present review, we summarize the current clinical evidence on DDIs of new anti FXI with CYP450/P-gp inhibitors and inducers and indicate potential differences with DOAC anti FXa."

Journal • Review • Acute Coronary Syndrome • Atrial Fibrillation • Cardiovascular • Venous Thromboembolism

Factor XI inhibitors in early clinical trials: a meta-analysis (ESC 2023) - " Eight RCTs testing FXI inhibitors (ISIS 416858, osocimab, abelacimab, milvexian, asundexian) and enrolling 9,216 patients were included. Results of this meta-analysis on FXI inhibitors suggest increased safety and efficacy compared with enoxaparin and modest increased safety compared with DOACs. The use of FXI inhibitors in adjunct to antiplatelet therapy versus placebo appears to be associated with a dose-dependent increase in bleeding without any difference in efficacy."

Retrospective data • Cardiovascular

Factor XI inhibitors in early clinical trials: a meta-analysis. (PubMed, Thromb Haemost) - "Results of this meta-analysis on FXI inhibitors suggest increased safety and efficacy compared with enoxaparin and modest increased safety compared with DOACs. The use of FXI inhibitors in adjunct to antiplatelet therapy versus placebo appears to be associated with a dose-dependent increase in bleeding without any difference in efficacy."

Journal • Retrospective data

Pharmacotherapy for stroke prevention in nonvalvular atrial fibrillation: current strategies and future directions. (PubMed, Expert Opin Pharmacother) - "Several oral (asundexian, milvexian) and parenteral (abelacimab, osocimab, xisomab, IONIS-FXI, fesomersen) factor XIa inhibitors are under development...Non-anticoagulant drugs, such as colchicine, metformin and dronedarone, also being investigated to reduce the burden of NVAF and cardioembolic stroke. Additional clinical data are needed to more clearly define the role of these drugs for stroke prevention in NVAF."

Journal • Atrial Fibrillation • Cardiovascular • Ischemic stroke

PK/PD modelling of FXI antisense oligonucleotides to bridge the dose-FXI activity relation from healthy volunteers to end-stage renal disease patients. (PubMed, CPT Pharmacometrics Syst Pharmacol) - "IONIS-FXI (BAY2306001) is an antisense oligonucleotide that inhibits the synthesis of coagulation factor XI and has been investigated in healthy volunteers and end-stage renal disease (ESRD) patients. FXI-LICA (BAY2976217) shares the same RNA sequence as IONIS-FXI but contains a GalNAc-conjugation that facilitates asialoglycoprotein receptor (ASGPR)-mediated uptake into hepatocytes...The model was then used to predict dose dependent steady-state FXI activity following repeat once-monthly doses of FXI-LICA in a virtual ESRD patient population. Under the assumption of similar ASGPR expression in ESRD patients and healthy volunteers, doses of 40mg, 80mg, and 120mg FXI-LICA are expected to cover the target range of clinical interest for steady-state FXI activity in the Phase 2b study of FXI-LICA in ESRD patients undergoing hemodialysis."

Clinical • Journal • PK/PD data • Chronic Kidney Disease • Nephrology • Renal Disease • ASGR • MUC4

Inhibition of coagulation factor XI decreases cardiac inflammation and impairs survival in a mouse model of myocardial infarction (GTH 2020) - "We effectively reduced coagulation factor FXI (FXI) levels by repetitive injections of FXI antisense oligonucleotide (FXI ASO)... Lowering FXI levels impaired cardiac remodeling with an increase in mortality post MI. FXI and thrombin are a putative link between the coagulation system and the immune response in cardiac remodeling post MI."

F2 • ITGAM

The Safety and Efficacy of Novel Agents Targeting Factors XI and XII in Early Phase Human Trials. (PubMed, Semin Thromb Hemost) - "Several drugs are under development for this purpose, including: ISIS 416858, a FXI antisense oligonucleotide which impairs hepatic synthesis of FXI; MAA868, a monoclonal antibody that binds the procoagulant enzymatic site of both zymogen and activated FXI (FXIa); BAY 1213790, a monoclonal antibody that binds the procoagulant enzymatic site of FXIa only; and AB023, a monoclonal antibody that inhibits activated FXII-mediated activation of FXI, along with two small molecules in clinical trials. Other benefits of some of these drugs include once-monthly dosing and safety in patients with renal or hepatic impairment, while others offer quickly metabolized parenteral options, thus providing more convenient and widely available anticoagulation options. Though still far from the marketplace, drugs targeting FXI and FXII have the potential to usher in a new era of anticoagulation therapy."

Clinical • Journal

Antithrombotic Agents. (PubMed, Circ Res) - "The aims of this article are to review the results of recent trials aimed at enhancing the benefit-risk profile of antithrombotic therapy and explain how these findings are changing our approach to the management of arterial and venous thrombosis. Focusing on these 2 aspects of thrombosis management, this article discusses 4 advances: (1) the observation that in some indications, lowering the dose of some direct oral anticoagulants reduces the risk of bleeding without compromising efficacy, (2) the recognition that aspirin is not only effective for secondary prevention of atherothrombosis but also for prevention of venous thromboembolism, (3) the finding that dual pathway inhibition with the combination of low-dose rivaroxaban to attenuate thrombin generation plus aspirin to reduce thromboxane A2-mediated platelet activation is superior to aspirin or rivaroxaban alone for prevention of atherothrombosis in patients with coronary or peripheral artery disease, and (4) the..."

Journal

Inhibition of Coagulation Factor XI Suppress Progression of Atherosclerosis (AHA 2019) - "We administered saline (control), anti-FXI antibody that inhibits FXI activation by FXII (14E11; 4mg/kg), or GalNAc-conjugated FXI antisense oligonucleotide that reduces FXI synthesis (FXI-ASO; 7.5mg/kg) weekly to 8-week-old LDLR -/- mice fed a high-fat diet (HFD) for 8 weeks...Our data support a scenario whereby FXI activation induces structural changes in endothelial cells to increase their permeability. Increased endothelial permeability has been shown to enhance infiltration of cellular and acellular material into the artery wall, which can promote early plaque formation, and contribute to the pathogenesis of atherosclerosis."

Late-breaking abstract • CDH5 • F2

A Study of ISIS 416858 Administered Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis (clinicaltrials.gov) - P2; N=213; Completed; Sponsor: Ionis Pharmaceuticals, Inc.; Active, not recruiting ➔ Completed

Clinical • Trial completion

Inhibition of Coagulation Factor XI Decreases Cardiac Inflammation and Impairs Survival in a Mouse Model of Myocardial Infarction (ISTH 2019) - "...We effectively reduced coagulation factor FXI (FXI) levels by repetitive injections of FXI antisense oligonucleotide (FXI ASO) Compared to scrambled ASO injected controls, FXI-ASO injected mice had significantly increased mortality 3d post MI (10% vs. 30%) and a worse left ventricular ejection fraction as well as increased wall motion score index measured by high-frequency ultrasound imaging... Lowering FXI levels impaired cardiac remodeling with an increase in mortality post MI. FXI and thrombin are a putative link between the coagulation system and the immune response in cardiac remodeling post MI."