CAD-1005 / Veralox Therap, Cadrenal Therapeutics - LARVOL DELTA

Comparing the Antiplatelet and Antithrombotic Effects of CCG263719 and SLUG001, Second Generation 12-Lipoxygenase Inhibitors, to ML355 (AHA 2026) - "Abstract is embargoed at this time."

Inflammation

THE 12‑LOX INHIBITOR ML355 SUPPRESSES PANCREATIC CANCER PROGRESSION VIA MACROPHAGE‑DEPENDENT REVERSAL OF M2 POLARIZATION (UEGW 2026) - No abstract available

Oncology • Pancreatic Cancer • Solid Tumor

High-Density Co-Based Single-Atom Nanozymes Alleviate Myocardial Ischemia-Reperfusion Injury by Disrupting the Cycle of Oxidative Stress-Ferroptosis-Inflammatory Response. (PubMed, Angew Chem Int Ed Engl) - "In addition, the combination with ML355 could specifically block the p53-mediated ferroptosis process by inhibiting ALOX12 activity. Mechanistically, the synergistic effect can significantly alleviate lipid peroxidation and oxidative stress injury in cardiomyocytes, and ultimately break the vicious cascade cycle of oxidative stress, ferroptosis and inflammatory response, and realize effective protection against MIRI."

Journal • Cardiovascular • Inflammation • Myocardial Ischemia • Reperfusion Injury • AVEN • CAT • GPX4

Cadrenal Therapeutics’ Late-Breaking Phase 2 Data Demonstrate Greater Than 25% Reduction in Thrombotic Events in HIT for First-in-Class 12-LOX Inhibitor CAD-1005 at ISTH 2026 Congress (GlobeNewswire) - "Unlike standard-of-care anticoagulants that only reduce thrombin generation, CAD-1005 is designed to directly block the underlying 12-LOX immune signaling loop that drives antibody-mediated platelet activation....Patients treated with CAD-1005 experienced a reduction of more than 25% in new or worsening thrombotic events compared with the placebo arm (50% vs. >75%), despite the study not being sufficiently powered for statistical significance....No serious adverse events attributable to CAD-1005, no major bleeding in SRA+ patients, and no deaths. Treatment with CAD-1005 was associated with fewer thromboembolic events without an increase in major bleeding."

Late-breaking abstract • P2 data • Hematological Disorders • Thrombocytopenia

12-Lipoxygenase Inhibition with VLX-1005 in Heparin-Induced Thrombocytopenia (ISTH 2026) - No abstract available

Late-breaking abstract • Hematological Disorders • Thrombocytopenia

Icosapent Ethyl Attenuates Thrombosis via EPA-Dependent, 12-Lipoxygenase–Mediated Platelet Inhibition (ISTH 2026) - "To assess 12-LOX dependence, platelets were pretreated with the 12-LOX inhibitor ML355 prior to incubation with EPA or 12-HEPE and subsequent analysis of thrombin-induced aggregation. This work provides mechanistic insight into the clinical efficacy of IPE and supports a platelet-centric pathway linking EPA metabolism to reduced thrombotic risk in cardiovascular disease. DOI*10.1016/j.rpth.2026.105259"

Cardiovascular • Hematological Disorders • Thrombosis • ALOX15

Cadrenal Therapeutics Announces up to $8.8 Million Private Placement Priced At-The-Market Under Nasdaq Rules (GlobeNewswire) - "The aggregate gross proceeds to the Company from the offering are expected to be $3 million, before deducting placement agent fees and other offering expenses....Net proceeds anticipated to extend cash runway into first quarter of 2027; if warrants are exercised in full for cash, it is anticipated that the cash runway would extend into second half of 2027 to advance partnering opportunities for tecarfarin in Kawasaki Disease (potential rare pediatric disease designation) and CAD-1005 in CSA-AKI and HIT."

Commercial • Acute Kidney Injury • Thrombocytopenia • Vasculitis

At the upcoming BIO International Convention, Cadrenal will present a dual-track portfolio strategy designed to maximize value for potential partners (GlobeNewswire) - "The Global Pharma Track: Focusing on CAD-1005, a first-in-class 12-LOX inhibitor...CAD-1005 is Phase 3-ready for Heparin-Induced Thrombocytopenia (HIT) and is advancing into a Phase 2a trial for Cardiac Surgery-Associated Acute Kidney Injury (CSA-AKI); The Regional & Rare Disease Track: Focusing on tecarfarin for Kawasaki disease...This program offers an efficient clinical trial design and strong geographic synergy, particularly for Japanese and East Asian pharmaceutical companies, where the incidence of Kawasaki disease is historically 10 to 15 times higher than in Western nations."

Pipeline update • Cardiovascular • Inflammation • Nephrology • Thrombocytopenia • Vasculitis

12-Lipoxygenase (12-LOX) plays a key role in the hyperinflammatory response caused by SARS-CoV-2. (PubMed, mBio) - "The use of VLX-1005, a selective 12-LOX inhibitor, significantly improved survival and reduced inflammatory damage in a mouse model, highlighting its therapeutic potential. These findings not only deepen our understanding of COVID-19 pathogenesis but also position 12-LOX as a promising intervention target, offering a new avenue to mitigate the effects of cytokine storms in severe cases."

Journal • Infectious Disease • Inflammation • Metabolic Disorders • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • ALOX15 • LOX

VLX-1005, but not argatroban, prevents ITAM-mediated platelet activation and heparin-induced thrombocytopenia. (PubMed, Blood Vessel Thromb Hemost) - "This study demonstrates that inhibition of 12-LOX might be an effective intervention for preventing ITAM-regulated platelet activation, such as in HIT, and is independent of argatroban effects in blood. Importantly, VLX-1005 prevents platelet activation and does not increase the bleeding risk associated with direct thrombin inhibitors, such as argatroban."

Journal • Cardiovascular • Hematological Disorders • Thrombocytopenia • Thrombosis • ALOX15

Inhibition of Endothelial ALOX12 Mitigates Cerebral Ischemia-Reperfusion Injury by Suppressing 12-HETE. (PubMed, Free Radic Biol Med) - "Endothelial localization and functional contribution were further assessed by microvessel-parenchyma fractionation, the selective ALOX12 inhibitor ML355, and endothelial-targeted AAV-BR1-mediated Alox12 knockdown...Clinically, plasma 12-HETE levels were significantly elevated in AIS patients and positively correlated with stroke severity (NIHSS). Together, these findings support endothelial ALOX12-12-HETE signaling as a redox-active angiocrine pathway contributing to multicellular neurovascular injury after cerebral I/R and highlight ALOX12 inhibition as a potential therapeutic strategy."

Journal • Cardiovascular • Inflammation • Ischemic stroke • Reperfusion Injury • KEAP1

Cadrenal Therapeutics Highlights Research Supporting 12-LOX Inhibition in Reducing Inflammation in Obesity and Type 2 Diabetes (The Manila Times) - "In the setting of obesity, 12-LOX overexpression leads to: Adipocyte dysfunction following recruitment of pro-inflammatory macrophages into adipose tissue triggering an inflammatory reaction that impairs tissue insulin sensitivity; Elevated 12-LOX activity in the pancreas causes oxidative stress and -cell dedifferentiation, hallmarks of Type 2 Diabetes progression....In preclinical models, oral administration of CAD-1005 (formerly VLX-1005) demonstrated significant therapeutic benefits, including improved glycemic control, reduced pancreatic β-cell loss, reduced numbers of inflammatory cells in adipose (fat) and pancreatic tissues, and lower levels of pro-inflammatory cytokines in adipose tissues."

Preclinical • Obesity • Type 2 Diabetes Mellitus

A Phase 2 Study of VLX-1005 Versus Placebo in Suspected Heparin Induced Thrombocytopenia (clinicaltrials.gov) - P2 | N=24 | Terminated | Sponsor: Veralox Therapeutics | N=60 ➔ 24 | Trial completion date: Mar 2025 ➔ Nov 2025 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2024 ➔ Nov 2025; Veralox Therapeutics Business Decision.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hematological Disorders • Thrombocytopenia

Non-Enzymatic Role of Platelet 12-LOX in Platelet Activation (ASH 2023) - "Finally, to determine if the association pattern of these proteins with 12-LOX is disrupted in the presence of a 12-LOX inhibitor already shown to limit platelet activation and which is currently in clinical trials for treatment of HIT (ML355/VLX-1005), we were able to demonstrate that the inhibitor appears to lock the protein complex into place...12-LOX interacts with Integrin β3, Talin-1 and cytoskeletal proteins. Furthermore, the dynamic movement of the proteins in this complex into and out of association with 12-LOX is essential for normal platelet activation suggesting 12-LOX plays an important non-enzymatic role in regulation of agonist-mediated platelet activation."

Cardiovascular • ACTR2 • ALOX15 • GSN • TLN1

Loss of 12-Lipoxygenase Improves the Post-Transfusion Function of Stored Platelets (ASH 2023) - "Inhibition of cyclooxygenase-1 (COX-1) with acetylsalicylic acid abrogated both increased integrin activation and thromboxane generation in stored 12-LOX-/- platelets, highlighting a critical role of this pathway for improved post-transfusion function. Consistent with our mouse studies, human platelets stored with the 12-LOX inhibitor, VLX-1005, showed increased integrin activation compared to vehicle-treated platelets upon transfusion in NOD/SCID mice. Conclusion Deleting 12-LOX improves the post-transfusion function of stored murine and human platelets by increasing thromboxane generation through a COX-1-dependent mechanism. Future studies should determine the feasibility and safety of 12-LOX-inhibited platelets transfused to humans."

Hematological Disorders • ALOX15

Phase 1, 3-Sequence Interaction Study of Intravenous Vlx-1005 and Argatroban Shows a Favorable Safety, Pharmacokinetic and Pharmacodynamic Profile in Healthy Volunteers (ASH 2024) - "The coadministration of VLX-1005 with argatroban had no impact on the effect of argatroban on aPTT in healthy human adult subjects. The Phase 2 ALATHEA (A study of VLX-1005 to evaLuAte Thrombocyte change in HEpArin Induced Thrombocytopenia) study of VLX-1005 in HIT is currently ongoing."

Clinical • P1 data • PK/PD data • Cardiovascular • Hematological Disorders • Thrombocytopenia • Thrombosis • ALOX15

The 12-LOX/12-HETE/GPR31 metabolic pathway promotes tumor-associated macrophage M2 polarization mediated pancreatic cancer development. (PubMed, PeerJ) - "In vivo and in vitro experiments were conducted using the 12-LOX inhibitor ML355 to investigate the role of the 12-LOX/12-HETE/GPR31 metabolic pathway in M2 macrophage polarization and tumor progression through flow cytometry, reverse transcription polymerase chain reaction (RT-PCR), 5-Ethynyl-20-deoxyuridine (EdU) assays, and Transwell experiments...Moreover, inhibiting 12-LOX reduced the co-cultured M2 macrophages. This study, through in vivo and in vitro experiments, reveals that the 12-LOX/12-HETE/GPR31 metabolic pathway affects the growth, migration, and invasion of PC by modulating M2 macrophage polarization patterns."

Journal • Oncology • Pancreatic Cancer • Solid Tumor • ALOX15

12-Lipoxygenase Inhibition Improves Glucose Homeostasis and Obesity-Associated Inflammation in Human Gene Replacement Mice (ENDO 2025) - "As a human-relevant model of obesity and T2D, we treated male B6.hALOX12 mice at 8 weeks of age with high-fat diet (HFD, 60% total calories from fat) and vehicle or VLX-1005, a potent and selective inhibitor of 12-LOX, given by oral gavage at 30 mg/kg/day for 10 weeks...Our mouse model provides a platform by which to investigate the pathophysiological role of 12-LOX in other metabolic diseases, such as atherosclerosis and metabolic-dysfunction associated steatotic liver disease. These findings also suggest that 12-LOX inhibition could serve as a therapeutic strategy for obesity and T2D."

Preclinical • Atherosclerosis • Cardiovascular • Diabetes • Genetic Disorders • Hepatology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus • ALOX15 • ITGAM • LOX • TNFA

12/15-lipoxygenases mediate toll-like receptor 4-dependent nociplastic pain hypersensitivity in female mice. (PubMed, Pain) - "Systemic inhibition of 12/15-LOX in female C57BL/6N mice with selective inhibitors ML355 (targeting 12-LOX-p) or ML351 (targeting 15-LOX-1) completely reversed allodynia and grip force deficits. 12/15-LMs also produce tactile allodynia when administered spinally (IT) or peripherally (paw intraplantar) at a subthreshold dose in a hyperalgesic priming model, similar to others' observations with a subthreshold dose of the cyclooxygenase metabolite prostaglandin E2. Collectively, these data suggest that 12/15-LOX enzymes contribute to peripheral and central pain hypersensitivity in rodents, with potential translatability as druggable targets across sexes and species using multiple reflexive and functional outcome measures."

Journal • Preclinical • Addiction (Opioid and Alcohol) • Immunology • Musculoskeletal Pain • Pain • ALOX15 • TLR4

Resolution of experimental malaria-associated acute respiratory distress syndrome is Alox12 independent and shows residual inflammation. (PubMed, Malar J) - "These findings suggest that while Nanostring profiling reveals critical processes in MA-ARDS resolution, targeting late-stage resolution alone by modulating SPM production is insufficient. This suggests that more effective, multi-targeted adjunctive therapies, alongside antimalarial drugs, may be required to improve survival and resolution upon MA-ARDS."

Journal • Acute Respiratory Distress Syndrome • Infectious Disease • Inflammation • Malaria • Pulmonary Disease • Respiratory Diseases

VLX-1005 regulates Heparin-induced thrombocytopenia (HIT) through inhibition of 12-LOX independent of thrombin activation. (ISTH 2025) - "Platelets in whole blood under arterial shear were prevented from adhering to collagen in the presence of VLX-1005 but not argatroban. Mice treated with VLX-1005 had no bleeding diathesis in a HIT model and were observed to result in significantly fewer platelets being activation in vivo."

Cardiovascular • Hematological Disorders • Thrombocytopenia • Thrombosis • ALOX15

12-Lipoxygenase Drives Hyperinflammatory Responses and Enhances COVID-19 Severity (IMMUNOLOGY 2025) - "Notably, 12-HETE was undetectable in VLX-1005-treated mice but significantly elevated in controls. These findings demonstrate that 12-LOX inhibition mitigates hyperinflammation and improves survival against severe COVID-19 infection.Keywords: Animals Rodent; Infections Viral; Molecules Lipid Mediators; Processes Inflammation; Tissues Lung"

Late-breaking abstract • Diabetes • Genetic Disorders • Infectious Disease • Inflammation • Metabolic Disorders • Novel Coronavirus Disease • Obesity • Respiratory Diseases • ALOX15 • LOX

12-Lipoxygenase inhibition improves glycemia and obesity-associated inflammation in male human gene replacement mice. (PubMed, Endocrinology) - "In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased β cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and T2D."

Journal • Preclinical • Diabetes • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • ALOX12 • ALOX15

12-Lipoxygenase inhibition improves glucose homeostasis and obesity-associated inflammation in human gene replacement mice. (PubMed, bioRxiv) - "In a distinct mouse model in which Alox15 was selectively deleted in myeloid cells, we observed decreased β cell dedifferentiation and reduced macrophage infiltration in both islets and adipose tissue, suggesting that the effects of VLX-1005 may relate to the inhibition of 12-LOX in macrophages. These findings highlight 12-LOX as a key factor in obesity-associated inflammation and suggest that 12-LOX inhibition could serve as a therapeutic strategy to improve glucose homeostasis and peripheral inflammation in the setting of obesity and T2D."

Journal • Preclinical • Genetic Disorders • Inflammation • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • ALOX12 • ALOX15

Veralox Therapeutics Expands Its Pipeline with the Exclusive Option to Acquire Nudge Therapeutics (PRNewswire) - "The addition of cGAS inhibitors complements the Company's focus on VLX-1005, which is expected to achieve clinical PoC in 2025....Veralox Therapeutics...announced today that it has entered into an exclusive agreement with Nudge Therapeutics to acquire the company and their preclinical cyclic AMP-GMP (cGAS) inhibitor compounds....'Veralox has unique experience with these assets which can be utilized to move the program forward quickly.'"

Licensing / partnership • New trial • Thrombocytopenia