VLX-1005 / Veralox Therap - LARVOL DELTA

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

12-Lipoxygenase inhibition delays onset of autoimmune diabetes in human gene replacement mice. (PubMed, JCI Insight) - "RNA sequencing analysis of isolated islets and polarized proinflammatory macrophages revealed significant alteration of cytokine-responsive pathways and a reduction in interferon response after VLX-1005 treatment. Our studies demonstrated that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes."

IO biomarker • Journal • Preclinical • Diabetes • Endocrine Disorders • Immunology • Metabolic Disorders • Obesity • Type 1 Diabetes Mellitus • ALOX12 • ALOX15 • PD-L1

Inhibition of ALOX12-12-HETE Alleviates Lung Ischemia-Reperfusion Injury by Reducing Endothelial Ferroptosis-Mediated Neutrophil Extracellular Trap Formation. (PubMed, Research (Wash D C)) - "Last, the administration of ML355, a targeted inhibitor of Alox12, mitigated lung IRI in both murine hilar clamp/reperfusion and rat left lung transplant models. Collectively, our study indicates ALOX12 as a promising therapeutic strategy for lung IRI."

Journal • Cardiovascular • Reperfusion Injury • Respiratory Diseases • Transplantation • HMGB1 • MYD88

12-Lipoxygenase inhibition suppresses islet immune and inflammatory responses and delays autoimmune diabetes in human gene replacement mice. (PubMed, bioRxiv) - "RNA sequencing of polarized proinflammatory macrophages showed that VLX-1005 significantly reduced the interferon response. Our studies demonstrate that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes."

IO biomarker • Journal • Preclinical • Diabetes • Immunology • Inflammation • Metabolic Disorders • Obesity • Type 1 Diabetes Mellitus • ALOX12 • ALOX15 • PD-1 • PD-L1

Extracellular vesicle lipid functions in inflammation and endothelial dysfunction (ISTH 2024) - "The functional relevance was investigated using RT-qPCR, cell adhesion assays, etc. 12-LOX was inhibited by ML355... The lipid profiles of macrophage-derived EVs differed largely depending on the polarization of the originating macrophages. M1-derived EVs showed decreased levels of arachidonic acid but increased levels of ARA-derived 12-and 15LOX and products, particularly 8/12-HETE. Both M1 EVs and 8/12 HETE induced expression of pro-inflammatory chemokines in target cells."

Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • ALOX15

Baicalein alleviates cisplatin-induced acute kidney injury by inhibiting ALOX12-dependent ferroptosis. (PubMed, Phytomedicine) - "This was the first study to confirm that baicalein regulates ferroptosis both in vitro and in vivo in cisplatin-induced AKI and to verify the regulatory effect of baicalein in folic acid-induced AKI. Our results reveal the critical role of ALOX12 in kidney damage and ferroptosis caused by cisplatin and emphasize the regulatory effect of baicalein on renal tubular epithelial cell ferroptosis mediated by ALOX12. Baicalein is an effective drug for treating AKI, and ALOX12 is a potential drug target."

Journal • Acute Kidney Injury • Nephrology • Renal Disease

Inhibition of ALOX12-12-HETE Alleviates Lung Ischemia Reperfusion Injury by Reducing Endothelial Ferroptosis-Mediated Neutrophil Extracellular Traps Formation (ISHLT 2024) - "Importantly, genetically inhibition of Alox12 significantly reduced lung injury, endothelial ferroptosis and NETs formation in vitro and in vivo. Moreover, ML355, a specific inhibitor of Alox12, could also alleviate lung IRI in both the mouse hilar clamp model and rat orthotopic lung transplantation model.Conclusion ALOX12-12HETE-mediated lung endothelial ferroptosis was an important driver for NETs formation and lung injury after ischemia reperfusion, while blocking ALOX12 is a promising treatment strategy for lung IRI."

Cardiovascular • Reperfusion Injury • Respiratory Diseases • Transplantation • HMGB1 • MYD88

Sustained activation of 12/15 lipoxygenase (12/15 LOX) contributes to impaired renal recovery post ischemic injury in male SHR compared to females. (PubMed, Mol Med) - "Our data demonstrate that sustained activation 12/15 LOX contributes to impaired renal recovery post ischemic injury in male and female SHR, although males are more susceptible on this mechanism than females."

Journal • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury • ALOX15

A Phase 2 Study of VLX-1005 Versus Placebo in Suspected Heparin Induced Thrombocytopenia (clinicaltrials.gov) - P2 | N=60 | Recruiting | Sponsor: Veralox Therapeutics | Not yet recruiting ➔ Recruiting | Initiation date: Jun 2023 ➔ Sep 2023

Enrollment open • Trial initiation date • Hematological Disorders • Thrombocytopenia

Loss of 12-Lipoxygenase Improves the Post-Transfusion Function of Stored Platelets. (PubMed, Arterioscler Thromb Vasc Biol) - "Deleting 12-LOX improves the post-transfusion function of stored murine platelets by increasing thromboxane generation through COX-1-dependent arachidonic acid metabolism. Future studies should determine the feasibility and safety of 12-LOX-inhibited platelets transfused to humans."

Journal • Cardiovascular • Hematological Disorders • Thrombosis • ALOX15

Cryo-EM structures of human arachidonate 12S-Lipoxygenase (12-LOX) bound to endogenous and exogenous inhibitors. (PubMed, Blood) - "The active site of the 12-LOX tetramer is occupied by an endogenous 12-LOX inhibitor, a long-chain acyl-Coenzyme A. Additionally, we found that the 12-LOX hexamer can simultaneously bind to arachidonic acid and ML355, a selective 12-LOX inhibitor that has passed a phase I clinical trial for treating heparin-induced thrombocytopenia and has received fast-track designation by the FDA. Overall, our findings provide novel insights into the assembly of 12-LOX oligomers, its catalytic mechanism, and small molecule binding, paving the way for further drug development targeting the 12-LOX enzyme."

Journal • Hematological Disorders • Thrombocytopenia • ALOX15

A novel strategy to combat the procoagulant phenotype in immune thrombotic thrombocytopenia using 12-LOX inhibition (ISTH 2023) - "Furthermore, we assessed the procoagulant phenotype and efficacy to treat HIT utilizing inhibitor of 12(S)-lipoxygenase (12-LOX), VLX-1005, previously reported to decrease platelet activation downstream of FcγRIIA and PAR4, using the triple allele 'HIT' mouse model... IIA-Par4+/+ mice given αCD9 were severely thrombocytopenic, with extensive platelet-fibrin deposition in the lung. In contrast, IIA-Par4-/- mice had negligible thrombocytopenia or pulmonary platelet-fibrin thrombi. In human platelets, we observed that PAR1, PAR4, and FcγRIIA each contributed to the procoagulant phenotype, via receptor-specific increases in cytosolic Ca2+."

Cardiovascular • Hematological Disorders • Thrombocytopenia • Thrombosis • ALOX15

Novel Strategy to Combat the Procoagulant Phenotype in Heparin-Induced Thrombocytopenia Using 12-LOX Inhibition. (PubMed, Arterioscler Thromb Vasc Biol) - "These data demonstrate for the first time the need for dual platelet receptor (PAR [protease-activated receptor] and FcγRIIA) stimulation for fibrin formation in HIT in vivo. These results extend our understanding of HIT pathophysiology and provide a scientific rationale for targeting the procoagulant phenotype as a possible therapeutic strategy in HIT."

Journal • Cardiovascular • Hematological Disorders • Thrombocytopenia • Thrombosis • ALOX15 • CD9