glenzocimab (ACT 017) / Acticor Biotech, China Medical System - LARVOL DELTA

Blocking platelet glycoprotein VI (GPVI) as a promising anti-thrombotic treatment. (PubMed, Drug Discov Today) - "This review introduces the mechanism of GPVI in thrombosis and highlights two investigational GPVI-targeting drugs (glenzocimab and Revacept), summarizing current evidence and future directions for this novel anti-thrombotic approach. The figure is created with BioRender. Teaser: This review highlights the multifaceted roles of GPVI in thrombosis, inflammation, and cancer, while summarizing the latest advances in GPVI-targeted drug development, offering new insights for therapeutic intervention in related diseases."

Journal • Review • Cardiovascular • Hematological Disorders • Infectious Disease • Ischemic stroke • Myocardial Infarction • Novel Coronavirus Disease • Oncology • Thrombosis

Reticulated platelets in coronary artery disease: a multidimensional approach unveils prothrombotic signalling and novel therapeutic targets. (PubMed, Eur Heart J) - "This study provides the first mechanistic explanation for RP hyperreactivity, revealing a distinct molecular profile and identifying GPVI and PI3K inhibition as promising targets for tailored antiplatelet therapy in CAD patients with elevated RPs."

Journal • Cardiovascular • Coronary Artery Disease • Hematological Disorders • Thrombosis • ITGA2B • SYK

Glenzocimab for reperfusion in the setting of endovascular therapy for brain infarction: GREEN study. (PubMed, J Neurointerv Surg) - P2/3 | "This is the first randomized trial evaluating the efficacy of glenzocimab with EVT. This prospective trial aims to determine whether glenzocimab with EVT improves functional outcome."

Journal • Cardiovascular • Hematological Disorders • Ischemic stroke • Thrombosis

Glycoprotein VI is a receptor for the PF4/anti-PF4 IgG complex and contributes to platelet activation in HIT. (PubMed, J Thromb Haemost) - "GPVI functions as a receptor for PF4/anti-PF4 IgG immune complexes, engaging FcγRIIA and contributing to platelet activation in HIT."

Journal • Cardiovascular • Hematological Disorders • Thrombocytopenia • Thrombosis

GALICE: Glenzocimab in Anterior Stroke With Large Ischemic Core Eligible for Endovascular Therapy (clinicaltrials.gov) - P2/3 | N=304 | Not yet recruiting | Sponsor: Fondation Ophtalmologique Adolphe de Rothschild | Trial completion date: Oct 2028 ➔ Oct 2030 | Trial primary completion date: Oct 2028 ➔ Oct 2030

Trial completion date • Trial primary completion date • Cardiovascular • Ischemic stroke

A microfluidic model of thromboinflammation integrating platelet secretion fibrin formation and NETosis in flowing human blood suitable for testing potential therapies (ISTH 2025) - "The following treatments were tested: glenzocimab (anti-GPVI), eptifibatide (anti-GPIIbIIIa), FXII900 (FXIIa inhibitor), and anti-tissue factor antibody. Hyperglycemia led to an exacerbation and acceleration of platelet activation, coagulation, and channel occlusion, in association with a marked formation of neutrophil extracellular traps. Combined inhibition of GPVI and FXIIa, or PPACK inhibition of thrombin, fully prevented platelet secretion and subsequent fibrin formation in both normoglycemic and hyperglycemic conditions, as well as NETosis in hyperglycemic conditions."

Cardiovascular • Diabetes • Inflammation • Ischemic stroke • ANXA5

GPVI is a receptor for the PF4/anti-PF4 IgG complex and mediates platelet activation in HIT (ISTH 2025) - "Notably, the affinity of PF4 for GPVI is significantly increased when PF4 is complexed with the HIT antibody KKO, but not RTO and other anti-PF4 antibodies, with a dissociation constant (Kd) in the nanomolar range. Additionally, platelet aggregation induced by PF4/KKO, of HIT sera, is reduced by both a polyclonal anti-GPVI antibody and glenzocimab, a high-affinity humanized antibody fragment (Fab) targeting GPVI."

Cardiovascular • Hematological Disorders • Immune Thrombocytopenic Purpura • Thrombocytopenia • Thrombocytopenic Purpura • Thrombosis

IMPACT OF ANTI-PLATELET AND ANTI-COAGULANT THERAPIES IN A MICROFLUIDIC MODEL OF VENULAR MICROTHROMBOSIS IN ISCHEMIC STROKE (ESOC 2025) - "The blood was preincubated with antiplatelets: Glenzocimab (GPVI), Eptifibatide (GPIIbIIIa), and anticoagulants: FXII900 (FXIIa) and a tissue factor antibody. We have thus developed a model of microthrombosis that is dependent on platelet procoagulant activity, where GPVI activates the contact pathway via polyphosphate release. These findings, aligned with animal models, suggest targeting the GPVI-contact pathway axis as a therapeutic strategy for microthrombosis. Future studies will validate these results in a murine tMCAO model."

Cardiovascular • Ischemic stroke • Thrombosis

Glycoprotein VI inhibitors: glenzocimab and EMA601 two inhibitory Fabs. (PubMed, Eur Heart J) - No abstract available

Journal

EMA601 and glenzocimab: two glycoprotein VI inhibitory Fabs with different potency. (PubMed, Eur Heart J) - No abstract available

Journal

Comparative Effects of Glenzocimab and Eptifibatide on Bleeding Severity in 2 Mouse Models of Intracranial Hemorrhage. (PubMed, J Am Heart Assoc) - "Unlike eptifibatide, glenzocimab is safe in the setting of ICH. These results suggest that glenzocimab could be administered upon suspicion of ischemic stroke, before assessment of its ischemic nature, thus opening the way to hastening of treatment initiation."

Journal • Preclinical • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Diabetes • Hematological Disorders • Ischemic stroke • Reperfusion Injury

New Targets for Antithrombotic Medications: Seeking to Decouple Thrombosis from Hemostasis. (PubMed, J Thromb Haemost) - "Among the factor XI/XIa inhibitors of coagulation, a parenterally administered monoclonal antibody (abelacimab) and two orally administered small molecule inhibitors (asundexian, milvexian) are collectively being studied in patients with atrial fibrillation, cancer-associated venous thromboembolism, acute coronary syndrome, and ischemic stroke. One parenterally administered glycoprotein VI antiplatelet agent (glenzocimab) is currently being studied in patients with ischemic stroke. If shown to be efficacious and safe in ongoing phase 3 studies, both classes of emerging antithrombotic agents have the potential to greatly improve outcomes for patients with challenging thrombotic conditions."

Journal • Review • Acute Coronary Syndrome • Atrial Fibrillation • Cardiovascular • Chronic Kidney Disease • Hematological Disorders • Ischemic stroke • Nephrology • Oncology • Renal Disease • Thrombosis • Venous Thromboembolism

Ischemia/reperfusion injury in acute human and experimental stroke: focus on thrombo-inflammatory mechanisms and treatments. (PubMed, Neurol Res Pract) - "The fact that the significance of I/R injury in AIS has recently been formally established and given the decisive role of platelet-leukocytes interactions herein, new avenues for adjunct stroke treatments emerge. Adjusted study designs to increase the probability of success are of outmost importance and we look forward from what can be learned from the so far unpublished, presumbably negative ACTISAFE and MOST trials."

Journal • Review • Cardiovascular • Inflammation • Ischemic stroke • Reperfusion Injury • TLR4

Platelet collagen receptors and their role in modulating platelet adhesion patterns and activation on alternatively processed collagen substrates. (PubMed, Thromb Res) - "To inhibit platelet-collagen interactions, combinations of monoclonal antibodies 6B4 and 6F1, targeting GPIbα and α2β1, respectively, were used, along with the therapeutic collagen receptor GPVI antibody glenzocimab...Interestingly, upon investigating combined inhibition of GPIb and α2β1, an additive inhibitor effect of 6F1 was observed on P-selectin expression and PS-exposure on acid soluble collagen but not HORM collagen at 1600s-1, suggesting that the acid soluble collagen is well suited to study reinforcing functions of collagen receptors. Overall, this study highlights the potential advantages of using alternative collagen surfaces beyond the conventional HORM collagen to detect nuanced collagen receptor dependencies, which may prove valuable in evaluating anti-platelet medication."

Journal • Cardiovascular • Hematological Disorders • Thrombosis

The humanized platelet glycoprotein VI Fab inhibitor EMA601 protects from arterial thrombosis and ischaemic stroke in mice. (PubMed, Eur Heart J) - "EMA601 is a conceptually novel and promising anti-platelet agent to efficiently prevent or treat arterial thrombosis and thrombo-inflammatory pathologies in humans at risk."

Journal • Preclinical • Cardiovascular • Hematological Disorders • Inflammation • Ischemic stroke • Thrombosis

ACTISAVE: ACuTe Ischemic Stroke Study Evaluating Glenzocimab Used as Add-on Therapy Versus placEbo (clinicaltrials.gov) - P2/3 | N=438 | Completed | Sponsor: Acticor Biotech | Active, not recruiting ➔ Completed | Trial completion date: Jan 2024 ➔ Apr 2024 | Trial primary completion date: Jan 2024 ➔ Apr 2024

Trial completion • Trial completion date • Trial primary completion date • Cardiovascular • Ischemic stroke

EMA601, a Novel Humanised Fab Inhibits Platelet Glycoprotein VI with Unprecedented Potency and Protects Mice from Arterial Thrombosis and Ischemic Stroke (ISTH 2024) - "Emf6.1Fab (KD: 0.427 nM) blocked GPVI function in human and hGP6tg/tg mouse platelets in multiple assays in vitro at concentrations ≥5 µg/mL. Emf6.1Fab (4 mg/kg)-treated hGP6tg/tg mice showed potent hGPVI inhibition ex vivo and were profoundly protected from arterial thrombosis as well as from cerebral infarct growth after tMCAO, whereas tail-bleeding times remained unaffected. Emf6.1Fab binds to a so far undescribed membrane proximal epitope in GPVI."

Late-breaking abstract • Preclinical • Cardiovascular • Hematological Disorders • Inflammation • Ischemic stroke • Thrombosis

Targeting GPVI with glenzocimab in COVID-19 patients: Results from a randomized clinical trial. (PubMed, PLoS One) - P2, P2/3 | "Therapeutic GPVI inhibition assessment during COVID-19 was conducted in response to a Public Health emergency. Glenzocimab in coagulopathic patients under therapeutic heparin was neither associated with increased bleeding, nor SAE. Clinical impact of glenzocimab on COVID-19 ARDS was not demonstrated. A potential role for GPVI inhibition in other types of ARDS deserves further experimentation. Glenzocimab is currently studied in stroke (ACTISAVE: NCT05070260) and cardiovascular indications."

Clinical • Journal • P2 data • Acute Respiratory Distress Syndrome • Cardiovascular • Hematological Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases

A novel experimental model of stable thrombosis: the anti-GPVI agent, glenzocimab, efficiently destabilizes an established thrombus (ISTH 2024) - "A double-injury of the mouse carotid induces the formation of a platelet-, fibrin- and red blood cell-rich thrombus, which remains stable for more than 45 min. We observed that cangrelor, which targets P2Y12, and eptifibatide, which blocks αIIbβ3, efficiently disaggregate the thrombus. We provide the first evidence that glenzocimab, promotes thrombus destabilization when administered to mice humanized for GPVI."

Cardiovascular • Hematological Disorders • Thrombosis

Glycoprotein VI is an interesting target to prevent early stent thrombosis in different arterial territories (ISTH 2024) - "DAPT (aspirin (50 µg/mL) + cangrelor (7.7 µg/mL)) efficiently prevented thrombus formation in coronary and femoral chambers. Real-time video-microscopy showed that blood perfusion trough a carotid, coronary or femoral stented macrofluidic chamber coated with HAPH, resulted in thrombus formation. Thrombi formed exclusively in the stented regions coated with HAPH. Scanning electron microscopy showed that the platelets within the thrombi were highly activated, as evidenced by shape change with filopodia extension."

Atherosclerosis • Cardiovascular • Dyslipidemia • Hematological Disorders • Thrombosis

Generation of new Affimers that modulate platelet GPVI-ligand interactions and selectively target GPVI dimer (ISTH 2024) - "Blood 2021) on the D1 domain, M17 targets a site on the D2 domain, overlapping in part with the glenzocimab binding site... Among the identified Affimers, D18, M17 and D22 bound GPVI dimer with nM affinities. These Affimers inhibited GPVI-collagen/CRP-XL/fibrinogen interaction and CRP-XL induced platelet aggregation. D18 bound GPVI dimer but not monomer."

Affimer reagents as tool molecules to modulate platelet GPVI-ligand interactions and specifically bind GPVI dimer. (PubMed, Blood Adv) - "Mapping of binding sites revealed that D22 binds a site that overlaps with Nb2 on the D1-domain, while M17 targets a site on the D2-domain, overlapping in part with the glenzocimab binding site, a humanized GPVI antibody Fab-fragment...D18 is dimer-specific and could be used as a tool to detect GPVI dimerization or clustering in platelets. A dimeric epitope regulating ligand binding was identified on the GPVI D2-domain, which could be used for the development of novel bivalent antithrombotic agents selectively targeting GPVI dimer on platelets."

Journal • Thrombosis

GALICE: Glenzocimab in Anterior Stroke With Large Ischemic Core Eligible for Endovascular Therapy (clinicaltrials.gov) - P2/3 | N=304 | Not yet recruiting | Sponsor: Fondation Ophtalmologique Adolphe de Rothschild

New P2/3 trial • Cardiovascular • Ischemic stroke

PATIENTS RANDOMIZED TO GLENZOCIMAB SUFFERED LESS HEMORRHAGIC TRANSFORMATION WITH GREATER BENEFIT IN LARGER BASELINE INFARCT CORE (ESOC 2024) - P1/2 | "Glenzocimab reduced likelihood and volume of HT in patients undergoing recanalization treatment, with a greater effect in patients with larger cores. Glenzocimab is a promising adjunct for large core patients undergoing recanalization treatment."

Clinical • Cardiovascular • Ischemic stroke

ACTISAVE CLINICAL TRIAL: EFFICACY AND SAFETY OF GLENZOCIMAB ON TOP OF THROMBOLYSIS WITH OR WITHOUT MECHANICAL THROMBECTOMY (ESOC 2024) - P1/2, P2/3 | "Results of ACTISAVE clinical trial will be presented at ESOC 2024"

Clinical • Cardiovascular • Ischemic stroke