gruticibart (AB023) / Aronora, Xoma - LARVOL DELTA

A novel cell-permeable LOXL2 inhibitor PAT-1251 potently suppresses biliary liver fibrosis via collagen crosslinking-dependent and -independent mechanisms. (PubMed, Hepatol Commun) - "While having comparable extracellular effects on collagen crosslinking in vivo, the cell-permeable LOXL2 inhibitor PAT-1251 exerted potent antifibrotic activity in hepatic progenitors and HSC cultures compared with the anti-LOXL2 antibody. PAT-1251 substantially outperformed the anti-LOXL2 antibody in the BALB/c. Mdr2-/- model of biliary fibrosis, suggesting that intracellular LOXL2 targeting is therapeutically important in addition to its well-characterized extracellular collagen crosslinking activity."

Journal • Cardiovascular • Fibrosis • Hepatology • Hypertension • Immunology • Liver Cirrhosis • Portal Hypertension • Primary Biliary Cholangitis • ABCB4

Evaluating reversal strategies for long-acting factor XI antibodies: RFVIIa®, FEIBA®, Kcentra®, novel FXI mutants, and an anti-idiotypic antibody (ASH 2025) - "BAY1831865), and theactive site binding FXIa inhibitor osocimab...With contact activation (ellagic acid or kaolin), the relative potency of thrombin inhibitionshifted: AB011 again showed the strongest inhibition on par with FXI-/- plasma, followed by gruticibart,and osocimab... FXI inhibitors produce anticoagulant effects across global coagulation assays that can bepartially or completely reversed by bypassing agents, particularly NovoSeven® and FEIBA®; however PT,TGA and viscoelastic testing also reveal the potential to generate a transient procoagulant/prothromboticstate if plasma concentrations of these commercially available agents are too high. The magnitude of theprocoagulant activity is dependent on the bypassing agent as well as the specific FXI inhibitor, suggestingthat reversal strategies should be tailored to the mechanism of the different FXI inhibitors (i.e. A2, A3, orcatalytic domain) to achieve optimal outcomes."

Hematological Disorders • Hemophilia • Rare Diseases

Factor XI Inhibition with AB023 Prevents Mechanical Valve Thrombosis in a Porcine Pulmonary Model Without Bleeding Events (AHA 2025) - "This is the first preclinical study using a validated in vivo model demonstrating that targeting FXI can successfully prevent mechanical valve thrombosis. Biweekly AB023 dosing preserved valve function in all test animals without bleeding complications, supporting its potential as a safer alternative to VKA therapy. These findings warrant further investigation in larger, longer-term studies and may form the basis for future clinical translation."

Preclinical • Cardiovascular • Hematological Disorders • Thrombosis

Genomic insights of the co-existence of blaOXA-23, blaOXA-91, blaNDM-1 harboring carbapenem-resistant Acinetobacter baumannii isolates from the intensive care units environment in Shanghai. (PubMed, J Glob Antimicrob Resist) - "The resistance rate of CRAB was slightly lower in 2023 compared to 2019. However, the emergence of pan-drug-resistant CRAB, along with the coexistence of carbapenemase-producing strains (OXA-23, OXA-51-like, and NDM-1) in 2023, underscore the dynamic progression of antimicrobial resistance (AMR) in this pathogen. These findings suggest a potential epidemiological shift characterized by clonal diversification alongside persistent carbapenemase-driven resistance mechanisms."

Journal • Critical care • Novel Coronavirus Disease

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

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

Preventing Coagulation of Extracorporeal System During Hemodialysis. (PubMed, Nephrol Nurs J) - "Low-dose/unfractionated heparin, low molecular weight heparin(s), airless tubing system, specially formulated dialyzers, continuous saline flushes, and contact activation inhibitor-AB023, combining heparin-coated dialyzers with intermittent saline flushes, are useful preventive measures. It is important to evaluate the individual needs of each patient in making decisions regarding treatment."

Journal • Review • Renal Disease

AB023. Early diagnosis and treatment lead to improve survival of glioblastoma patients. (PubMed, Chin Clin Oncol) - "Early diagnosis and surgery within 3 weeks from the initial symptoms are associated with improved patient survival. Early GBM treatment will be beneficial for patients with GBM. A short duration from the first hospital visit to the first surgery is essential in enhancing GBM patient prognosis."

Journal • Retrospective data • Brain Cancer • CNS Disorders • CNS Tumor • Epilepsy • Glioblastoma • Oncology • Solid Tumor

Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2. (PubMed, Cell Rep Med) - "Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffening. These findings have implications for the interpretation of the lack of efficacy of simtuzumab in clinical trials of fibrotic diseases."

Journal • Fibrosis • Immunology

Xisomab 3G3 for the Prevention of Catheter-Associated Thrombosis in Patients With Cancer Receiving Chemotherapy (clinicaltrials.gov) - P2 | N=9 | Terminated | Sponsor: OHSU Knight Cancer Institute | N=50 ➔ 9 | Recruiting ➔ Terminated; IP manufacturing issue

Enrollment change • Trial termination • Cardiovascular • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Plasmacytoma • Solid Tumor • Thrombosis

Factor XI Inhibition With Heparin Reduces Clot Formation in Simulated Pediatric Extracorporeal Membrane Oxygenation. (PubMed, ASAIO J) - "A roller-pump circuit circulated either 0.5 U/ml of unfractionated heparin alone or in combination with the anti-FXI immunoglobulin G (IgG) (AB023) for 6 hours or until clot formation caused device failure...AB023 plus heparin significantly reduced peak thrombin compared to heparin alone (123 vs. 217 nM; p < 0.01). Inhibition of contact pathway activation of FXI may be an effective adjunct to anticoagulation in extracorporeal life support."

Journal • Cardiovascular • Hematological Disorders • Pediatrics

Factor XI Inhibition for the Prevention of Catheter-Associated Thrombosis in Patients With Cancer Undergoing Central Line Placement: A Phase 2 Clinical Trial. (PubMed, Arterioscler Thromb Vasc Biol) - P2 | "Our objective was to evaluate the safety and efficacy of an anti-FXI mAb, gruticibart (AB023), in a prospective, single-arm study of patients with cancer receiving central line placement...These findings suggest that targeting FXI could represent a safe intervention to prevent catheter thrombosis. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04465760."

Journal • P2 data • Cardiovascular • Hematological Disorders • Oncology • Thrombosis • CRP

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

SPECT Imaging of Lysyl Oxidase-like 2 in a Model of Idiopathic Pulmonary Fibrosis. (PubMed, Mol Pharm) - "The bifunctional chelator DOTAGA-PEG-NH was chemoenzymatically conjugated to the murine antibody AB0023 using microbial transglutaminase, resulting in a degree of labeling (number of chelators per antibody) of 2.3. In conclusion, we report the first radioimmunotracer targeting the protein LOXL2 for nuclear imaging of IPF. The tracer showed promising results in a preclinical model of bleomycin-induced pulmonary fibrosis, with high lung uptake in fibrotic areas, and accounted for the antifibrotic activity of nintedanib."

Journal • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Pulmonary Disease • Respiratory Diseases

[VIRTUAL] Safety and Efficacy of the Contact Activation Inhibitor AB023 in Patients with End-Stage Renal Disease on Chronic Hemodialysis: A Phase 2, Double-Blind, Randomized, Placebo-Controlled Trial (ASH 2020) - P2 | "Anticoagulation with AB023 was well-tolerated and reduced clot formation within the HD circuit of ESRD patients. These findings suggest that inhibiting contact system activation could reduce medical device-initiated blood clot formation in patients."

Clinical • P2 data • Chronic Kidney Disease • Nephrology • Renal Disease • Thrombosis

CONTACT FACTOR XI INHIBITION IN A SIMULATED ECMO CIRCUIT WITH HUMAN WHOLE BLOOD (SCCM 2023) - "Our hypothesis is that Aronora Bio’s AB023 antibody, that blocks activation of Factor XI (FXI) by contact-activated Factor XII (FXIIa), will significantly reduce thrombin generation and clot formation in a simulated ECMO circuit using fresh heparinized human whole blood... Inhibition of contact pathway activation of Factor XI may be an effective adjunct to decrease systemic anticoagulation of extracorporeal life support. Novel anticoagulants would decrease cost, complications, and barriers to use of lifesaving ECMO."

Hematological Disorders • Respiratory Diseases

Factor XI Inhibition for the Prevention of Catheter-Associated Thrombosis in Cancer Patients Undergoing Central Line Placement: A Phase 2 Clinical Trial (ASH 2022) - "No catheter occlusions requiring alteplase occurred in either group during the first 14 days of observation. In total, 22 patients (11 in each study) were enrolled. Nine patients in the interventional cohort received AB023, 8 of which underwent surveillance ultrasound, and 10 patients in the control cohort underwent surveillance ultrasound (Table 2). Malignancies included pancreatic cancer (4/11), colorectal cancer (3/11), and lymphoma (2/11) in the interventional study, and lymphoma (4/11) colorectal cancer (3/11), and head and neck cancer (3/11) in the control study."

Clinical • P2 data • Cardiovascular • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Hematological Disorders • Hematological Malignancies • Hepatology • Immunology • Inflammation • Leukemia • Liver Failure • Lymphoma • Oncology • Pancreatic Cancer • Pulmonary Embolism • Respiratory Diseases • Solid Tumor • Thrombocytopenia • Thrombosis • Venous Thromboembolism • SELP

Aronora Announces Clinical Data to Be Presented at the 64th American Society of Hematology Annual Meeting (Yahoo Finance) - "Presentation to include clinical data from a phase 2 study of Gruticibart (AB023), a factor XI-targeted antibody being developed for the treatment and prevention of thrombosis and inflammation."

P2 data • Cardiovascular • CNS Disorders • Thrombosis

Inhibition of lysyl oxidase‑like 2 ameliorates folic acid‑induced renal tubulointerstitial fibrosis. (PubMed, Exp Ther Med) - "The present study evaluated the effect of LOXL2 inhibition using an inhibitory monoclonal antibody (AB0023) on tubulointerstitial fibrosis in a folic acid-induced tubulointerstitial fibrosis mouse model. Following transforming growth factor-β (TGF-β) challenge, LOXL2-deficient HK-2 cells exhibited significantly lower expression of the mesenchymal markers vimentin and fibronectin than control HK-2 cells. In conclusion, LOXL2 inhibition ameliorates renal fibrosis through the TGF-β/Smad signalling pathway."

Journal • Fibrosis • Immunology • Oncology • FN1 • SMAD4 • TGFB1 • VIM

Pharmacological reduction of coagulation factor XI reduces macrophage accumulation and accelerates deep vein thrombosis resolution in a mouse model of venous thrombosis. (PubMed, J Thromb Haemost) - "Pharmacologic targeting of FXI enhances the early stages of experimental venous thrombus resolution in wildtype CD1 mice, and may be of interest for future clinical evaluation of the antibody in DVT and PTS."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Immunology • Inflammation • Thrombosis • Venous Thromboembolism • CD31

[VIRTUAL] A Randomized, Double-blind, Placebo-controlled, Phase 2 Study Evaluating Safety and Efficacy of AB023 in Hemodialysis Patients (ISTH 2021) - P2 | "AB023 reduced potassium and iron entrapment in the dialyzers consistent with less blood entrapment during dialysis. Conclusions : Inhibiting contact-initiated FXI activation with AB023 was well-tolerated and reduced clot formation in the hemodialysis circuit in ESRD patients during hemodialysis."

Clinical • P2 data • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease • Thrombosis • CRP

Aronora Reports Positive Topline Data From Phase 2 Study of AB023 in Hemodialysis Patients (PRNewswire) - P2, N=27; NCT03612856; Sponsor: Aronora, Inc; “Aronora Inc…announced positive topline data from the Company's randomized placebo-controlled phase 2 clinical trial testing AB023 in end-stage renal disease patients on heparin-free hemodialysis....AB023 administration was not associated with increased bleeding at the vascular access site, or with any other drug-related adverse events. Occlusive clotting events that required hemodialysis circuit change-out were less frequent, and biomarkers of thrombosis and inflammation were lower after AB023 administration compared with pre-dosing levels. AB023 also reduced blood entrapment within the dialyzers, consistent with less blood clotting….Clinical trial data will also be presented at the XXIX Congress of the International Society on Thrombosis and Haemostasias (ISTH), taking place virtually July 17-21, 2021.”

P2 data • Renal Disease • Thrombosis

Contact Activation Inhibitor, AB023, in Heparin-Free Hemodialysis: Results of a Randomized Phase 2 Clinical Trial. (PubMed, Blood) - P2 | "AB023 also reduced potassium and iron entrapment in the dialyzers, consistent with less blood accumulation within the dialyzers. We conclude that despite the small sample size, inhibition of contact activation-induced coagulation with AB023 was well tolerated and reduced clotting within the dialyzer."

Clinical • Journal • P2 data • Chronic Kidney Disease • Hematological Disorders • Nephrology • Renal Disease • CRP

Grincamycins P-T: Rearranged Angucyclines from the Marine Sediment-Derived Streptomyces sp. CNZ-748 Inhibit Cell Lines of the Rare Cancer Pseudomyxoma Peritonei. (PubMed, J Nat Prod) - "Thus, in our effort to discover potential drug leads against the rare cancer pseudomyxoma peritonei (PMP), which currently lacks effective drug treatments, we screened extracts of marine actinomycete bacteria against the PMP cell line ABX023-1...To identify a candidate biosynthetic gene cluster (BGC) encoding the grincamycins, we sequenced the genome of the producing strain, Streptomyces sp. CNZ-748, and compared the BGCs detected with those linked to the production of angucyclines with different aglycon structures."

Journal • Preclinical • Oncology

Xisomab 3G3 for the Prevention of Catheter-Associated Thrombosis in Patients With Cancer Receiving Chemotherapy (clinicaltrials.gov) - P2; N=50; Recruiting; Sponsor: OHSU Knight Cancer Institute; Not yet recruiting ➔ Recruiting; Initiation date: Nov 2020 ➔ Feb 2021

Clinical • Enrollment open • Trial initiation date • Cardiovascular • Hematological Disorders • Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Plasmacytoma • Solid Tumor • Thrombosis