osocimab (BAY 1213790) / Xoma, Bayer, Aronora - LARVOL DELTA

Anticoagulation in Atrial Fibrillation: Is a Paradigm Shift From Xa to XIa Inhibitors on the Horizon? (PubMed, Cardiol Rev) - "The effective management of atrial fibrillation, particularly regarding the prevention of ischemic stroke and systemic embolism, has progressed with the introduction of direct oral anticoagulants, which have shown a reduction in bleeding risks when compared to warfarin. The oral factor Xa inhibitors, such as apixaban and rivaroxaban, are considered the first line for anticoagulation in cases of atrial fibrillation. Several factor XI inhibitors, including abelacimab, asundexian, osocimab, gruticibart, milvexian, and fesomersen, are currently undergoing clinical trials for similar therapeutic purposes...This review article aims to emphasize the recent trials evaluating these factor XI inhibitors with a special focus on abelacimab. Abelacimab may signify a promising advancement in anticoagulation therapy, providing potential advantages such as reduced gastrointestinal bleeding risks and the convenience of monthly dosing."

Journal • Atrial Fibrillation • Cardiovascular • Gastroenterology • Ischemic stroke

Compassionate Use of Osocimab in Preventing Thrombotic Complications Without Incremental Bleeding: A Case Report. (PubMed, TH Open) - "Being fully CVC-dependent since birth, our patient repeatedly developed catheter-related thrombosis (CRT) since infancy and was treated with daily low-molecular-weight heparin injections for more than 15 years...A short period of rivaroxaban treatment had to be stopped owing to acute gastrointestinal bleeding...Now, with 2.5 years of uninterrupted exposure outside of a clinical trial, this patient has experienced the longest duration of factor XIa inhibition to date. She continues to receive osocimab under the compassionate use program and maintains a positive change in her well-being and quality of life."

Journal • Cardiovascular • Developmental Disorders • Gastroenterology • Gastrointestinal Disorder • Gynecology • Hematological Disorders • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • Short Bowel Syndrome • Thrombosis • Venous Thromboembolism

Targeting factor XI as a compromise between thrombosis and bleeding. (PubMed, Cardiol J) - "They include: a) orally administered small molecule inhibitors such as milvexian and asundexian; b) monoclonal antibodies such as abelacimab, osocimab, and xisomab, which specifically bind and inactivate FXI; c) FXI-antisense oligonucleotide (FXI-ASO), which downregulate FXI synthesis at the mRNA level and reduce plasma FXI concentrations. Their development is an important step in the history of anticoagulant therapy, striving to find a balance between preventing thromboembolism and reducing bleeding risk, ultimately improving patient outcomes. In this context, a discussion on the characteristics of FXI inhibitors, a summary on data regarding the efficacy and safety of FXI inhibitors based on preclinical and clinical studies, and an outline of future perspectives regarding therapeutic strategies of FXI inhibition in venous thrombosis are presented in this study."

Journal • Cardiovascular • Hematological Disorders • Osteoporosis • Rheumatology • Thrombocytopenia • Thrombosis

Potential New Treatments for Chronic Kidney Diseases: A Concise Review. (PubMed, Curr Pharm Des) - "This concise review will shed light on the clinical trials of runcaciguat, cotadutide, osocimab, and Endothelin Receptor Antagonists (ERAs) in patients with CKD and/or ESKD. These drugs were retrieved following surveying the Clinical Trial database as well as the Pubmed database, both maintained by the US National Library of Medicine."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Transplantation

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

From the INVICTUS Trial to Current Considerations: It's Not Time to Retire Vitamin K Inhibitors Yet! (PubMed, Pharmaceuticals (Basel)) - "In this study, rivaroxaban failed to prove superiority over VKA in preventing the composite primary efficacy endpoints of stroke, systemic embolism, myocardial infarction, and death...Close to the heels of the dismal results of INVICTUS, an apixaban trial in prosthetic heart valves, PROACT-Xa, was also prematurely terminated due to futility...Multiple agents (monoclonal antibodies-e.g., osocimab, anti-sense oligonucleotides-e.g., fesomersen, and small molecule inhibitors-e.g., milvexian) have garnered positive data from phase II studies, and many have entered the phase III studies in AF/Venous thromboembolism. Future studies on conventional DOAC and new-generation DOAC will shed further light on whether DOAC can dethrone VKA in valvular heart disease."

Journal • Review • Atrial Fibrillation • Cardiovascular • Cerebral Hemorrhage • Heart Failure • Hematological Disorders • Myocardial Infarction • Venous Thromboembolism

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

Anticoagulation with osocimab in patients with kidney failure undergoing hemodialysis: a randomized phase 2 trial. (PubMed, Nat Med) - P2 | "These results suggest that osocimab is associated with a low risk of bleeding and is generally well tolerated in this population; findings that require confirmation in larger trials. ClinicalTrials.gov identifier, NCT04523220 ."

Journal • P2 data • Cardiovascular • Renal Disease

Venous Thromboembolism Prophylaxis in Major Orthopedic Surgeries and Factor XIa Inhibitors. (PubMed, Med Sci (Basel)) - "First-line options include low-molecular-weight heparins (LMWHs), direct oral anticoagulants, and aspirin. Second-line options consist of unfractionated heparin (UFH), fondaparinux, and warfarin. For most patients undergoing knee or hip arthroplasty, the initial agents recommended for the early perioperative period are LMWHs (enoxaparin or dalteparin) or direct oral anticoagulants (rivaroxaban or apixaban)...However, emerging factor XI(a) inhibitors, as revealed by a recent meta-analysis, have shown a substantial decrease in the occurrence of VTE and bleeding events among patients undergoing major orthopedic surgery. This discovery poses a challenge to the existing paradigm of anticoagulant therapy in this specific patient population and indicates that factor XI(a) inhibitors hold great promise as a potential strategy to be taken into serious consideration."

Journal • Review • Surgery • Cardiovascular • Hematological Disorders • Musculoskeletal Diseases • Orthopedics • Respiratory Diseases • 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

Development of new anticoagulant in 2023: Prime time for anti-factor XI and XIa inhibitors. (PubMed, J Med Vasc) - "The history of anticoagulation has evolved considerably from non-specific drugs (i.e., heparins and vitamin K antagonists, VKA) to agents that directly target specific coagulation factors (i.e., argatroban, fondaparinux and direct oral anticoagulants, DOAC). Based on epidemiological data with patients with inherited factor XI (FXI) deficiency and preclinical studies, FXI emerged as the most promising candidate target separating hemostasis from thrombosis. This review summaries the role of FXI and FXIa in hemostasis, provides evidence of initial success with FXI pathway inhibitors in clinical trials (such as IONIS-FXI, fesomersen, osocimab, abelacimab, milvexian, asundexian or xisomab 3G3) and highlights the opportunities and challenges for this next generation of anticoagulants."

Journal • Atrial Fibrillation • Cardiovascular • Hematological Disorders • Venous Thromboembolism

The Factor XIa Antibody Osocimab Combined with Enoxaparin Strongly Inhibits Clotting in Extracorporeal Circuits in vitro (ISTH 2023) - "Out of 40 subjects screened 34 (50% male, mean age 32 years (+/-9)) were enrolled in the study. Ten subjects were randomly assigned to the HD group, 12 to the ECMO group and 12 to the LVAD group. The addition of osocimab to enoxaparin significantly prolonged the time to filter clotting from 120min (IQR:105-150) to 180min (IQR:180-180) in HD circuits, from 127min (IQR:38-210) to 180min (IQR:69-240) in ECMO circuits and from 36min (IQR:18-59) to 113min (IQR:51-120) in LVAD circuits."

Preclinical

FACTOR XI-A INHIBITION BY OSOCIMAB IN PATIENTS WITH END-STAGE KIDNEY DISEASE ON HEMODIALYSIS (ESKD-HD) (ERA-EDTA 2023) - No abstract available

Clinical • Late-breaking abstract • Chronic Kidney Disease • Nephrology • Renal Disease

"💥Safety and efficacy of lower-dose and higher-dose osocimab versus placebo in the CONVERT study been presented by Prof Wolfgang #ERA23" (@iamnephrologist)

Clinical

News at XI: Moving Beyond Factor Xa Inhibitors. (PubMed, J Thromb Haemost) - "Currently available DOACs include dabigatran, which inhibits thrombin, and apixaban, edoxaban, and rivaroxaban, which inhibit factor (F) Xa...These new DOACs, which include asundexian and milvexian, inhibit FXIa, which is positioned in the intrinsic pathway of coagulation...These include fesomersen, an antisense oligonucleotide that reduces the hepatic synthesis of FXI, abelacimab, an antibody that binds FXI and blocks its activation, and osocimab, an FXIa inhibitory antibody. Focusing on these new agents, this paper (a) describes the unmet needs in oral anticoagulation therapy, (b) explains why FXI is a promising target for new oral anticoagulants, (c) reviews the phase 2 clinical data with the new agents and describes the ongoing phase 3 trials, and (d) provides perspective on the opportunities and challenges for FXI inhibitors."

Journal • Review • Cardiovascular • Hematological Disorders • Thrombosis • Venous Thromboembolism

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

End-stage Renal Disease (ESRD) Pilot Study (clinicaltrials.gov) - P1; N=55; Completed; Sponsor: Bayer; Active, not recruiting ➔ Completed

Clinical • Trial completion • Chronic Kidney Disease • Nephrology • Renal Disease

End-stage Renal Disease (ESRD) Pilot Study (clinicaltrials.gov) - P1; N=55; Active, not recruiting; Sponsor: Bayer; Recruiting ➔ Active, not recruiting

Clinical • Enrollment closed • Chronic Kidney Disease • Nephrology • Renal Disease

XOMA Highlights Recent Royalty Asset Portfolio Developments and Reports Third Quarter 2020 Financial Results (BioSpace) - "'Our partners continue to make advances in their missions to bring new therapies to patients in need'....'Another three partners announced the initiation of Phase 2 studies in the third quarter – Bayer’s osocimab CONVERT study in patients with kidney failure requiring hemodialysis...'"

Trial status • Renal Disease • Venous Thromboembolism

Title: Osocimab: A Novel Agent in Preventing Venous Thromboembolism. (PubMed, J Cardiovasc Pharmacol) - "Current guidelines recommend the direct acting oral anticoagulants, enoxaparin, fondaparinux, and warfarin as options for venous thromboembolism prevention. Phase 2 trials have identified that an optimal dose range, 0.6-1.2mg/kg, as a one-time dose pre- or post-operatively is effective in preventing thrombotic complications with minimal bleeding risk compared to standard of care for elective total knee arthroplasty patients. Future clinical development will be able to clearly outline the role this agent will play in the future."

Journal • Cardiovascular • Hemophilia • Orthopedics • Pain • Venous Thromboembolism

Turning Up to Eleven: Factor XI Inhibitors as Novel Agents to Maximize Safety and Maintain Efficacy in Thromboembolic Disease. (PubMed, Curr Probl Cardiol) - "Both osocimab and IONIS-FXI have been evaluated in patients undergoing orthopedic surgery and demonstrated superiority to enoxaparin without increasing major bleeding. Future studies with both these agents are ongoing, as well as the continued development of other inhibitors of factor XI. Early data regarding factor XI inhibition is encouraging as a potent anticoagulant and may offer a safer alternative compared to therapeutic currently available in contemporary practice for thromboembolic disease."

Clinical • Journal • Review • Cardiovascular • Hemophilia • Orthopedics

CONVERT: Study to Investigate the Safety of a Drug Called Osocimab at Low and High Doses in Adult Patients With Kidney Failure Requiring Regular Hemodialysis (clinicaltrials.gov) - P2; N=600; Recruiting; Sponsor: Bayer; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Cardiovascular • Chronic Kidney Disease • Renal Disease