varespladib (A-002) / Anthera Pharma, Ophirex - LARVOL DELTA

Structural and Pharmacological Analysis of a PLA2-like Toxin in Complex with the sPLA2 Inhibitor AZD2716: Comparisons to Varespladib. (PubMed, Biochimie) - "Although AZD2716 and varespladib bind to similar regions in both PLA2-like toxins and catalytic sPLA2s, they inhibit these proteins through distinct mechanisms due to differences in their functional sites. These findings highlight drug repurposing as a promising strategy for the development of complementary therapies to mitigate the severe local damage associated with snakebite envenoming but are generally applicable to drug discovery and repositioning strategies."

Journal

Endogenous "Time Bomb" - Mislocalized Phospholipase A2 as a Critical Mediator of Ultra-Rapid Mortality in Sepsis and Acute Lung Injury. (PubMed, Adv Sci (Weinh)) - "Based on these findings, a combination therapy comprising phospholipase (dioleoylphosphatidylserine) and an inhibitor (varespladib) was developed, which significantly improved survival rates from 0% to over 90% in mice with sepsis, acute lung injury, and PLA2 poisoning. This study provides critical theoretical foundations and intervention strategies for the clinical treatment of related diseases."

Journal • Acute Lung Injury • Infectious Disease • Inflammation • Pulmonary Disease • Respiratory Diseases • Septic Shock

The effect of the secretory phospholipases A2 from Gloydius blomhoffii and Gloydius halys venoms on hemostasis components in vitro. (PubMed, Biomed Khim) - "Whole G. halys and G. blomhoffii venoms and Varespladib added to them did not affect the extrinsic pathway of hemocoagulation, but inhibited the intrinsic pathway of human blood coagulation. The paradoxical effect of further enhancing the anticoagulant activity of G. halys and G. blomhoffii venoms with the sPLA2 inhibitor Varespladib could be determined by a stronger sPLA2 interaction with blood coagulation factor Xa after formation of the enzyme-inhibitor complex."

Journal • Preclinical

EBV Promotes Alveolar Trabecula Resorption via Extracellular Vesicle Remodeling by Group IIA Secreted Phospholipase A2. (PubMed, J Lipid Res) - "Treatment with the sPLA2 inhibitor varespladib reduced CTSK and RANKL expression in vitro and in vivo, confirming the role of sPLA2-IIA in osteoclastogenesis. Furthermore, sPLA2-IIA expression and metabolites were significantly elevated in EVs from gingival crevicular fluid of EBV-positive periodontitis patients. These findings suggest that sPLA2-IIA-mediated hydrolysis of EVs from EBV-infected cells contributes to alveolar bone loss, offering insights into therapeutic strategies targeting EBV and sPLA2-IIA to prevent periodontitis progression."

Journal • Dental Disorders • Epstein-Barr Virus Infections • Infectious Disease • Inflammation • Osteoporosis • Periodontitis • CSF1 • CTSK • TNFSF11

In vitro-in vivo discord: A preclinical study of AZD2716 and its racemate with comparison to varespladib for the development of snake venom sPLA2 inhibitors. (PubMed, Toxicon X) - "Additionally, the stereospecific AZD2716 did not provide the same survival advantage as the racemic mixture and neither molecule resulted in the same survival advantage as varespladib in vivo (p < 0.05), despite similar in vitro potency. These findings highlight the importance of following in vitro inhibition assays with preclinical studies in drug candidate selection for lead compounds and advancement to clinical development."

Journal • Preclinical

Chromobox2 inhibition: a novel activity of alisertib, an aurora A kinase inhibitor. (PubMed, Mol Cancer Ther) - "In vitro validation narrowed compounds of interest to raltitrexed, alisertib, GTX-007, LY315920, and PD0325901. Treatment with alisertib leads to decrease in H2AK119ub and shift in the immune tumor microenvironment. Alisertib efficacy in HGSC is dependent on functional CBX2 and cell target engagement confirms selectivity for CBX2, supporting that alisertib activity involves CBX2 inhibition."

Journal • Oncology • AURKA • CBX2

Revealing the rationale behind the differential neutralization of phospholipase A2 (PLA2) enzymes in snake and bee venom by varespladib (LY-315920), a small molecule PLA2 inhibitor. (PubMed, J Biomol Struct Dyn) - "VP showed significant neutralization of in vivo toxicity, generating reactive oxygen species and altering mitochondrial transmembrane potential induced by PLA2s from BFSV in the Caenorhabditis elegans model. However, such activities were not shown against BV-PLA2, indicating the limitations of broad-spectrum inhibitors like VP in neutralizing BV-PLA2."

Journal

Beyond Lipids and Platelets: A Review of Anti-Inflammatory Strategies in Secondary Prevention of Acute Coronary Syndromes. (PubMed, J Clin Med) - "Colchicine, now FDA-approved for cardiovascular risk reduction, lowered major adverse cardiovascular events in COLCOT and LoDoCo2. Canakinumab (IL-1β inhibition) reduced recurrent events in proportion to IL-6 and hsCRP suppression, while ziltivekimab (IL-6 inhibition) achieved profound biomarker reductions but remains investigational. Early-phase studies of anakinra (IL-1 receptor antagonist) and dapansutrile (oral NLRP3 inhibitor) showed anti-inflammatory effects in early trials, whereas varespladib and darapladib illustrated the challenges of targeting lipid-associated pathways...Additional emerging avenues include triptolidiol, dasatinib, and BTK or JAK/STAT inhibitors, while novel approaches, such as nanozyme delivery systems and CRISPR-based editing, extend the therapeutic horizon. This review highlights the potential of inflammation-targeted therapies to advance secondary prevention in ACS by integrating current evidence and perspectives on future therapeutic..."

Journal • Review • Acute Coronary Syndrome • Atherosclerosis • Cardiovascular • Coronary Artery Disease • Immunology • Inflammation • Myocardial Infarction • CRP • IL1B • NLRP3

Varespladib-Based Lipid Nanoparticles as Highly Efficient Anti-Inflammatory Agents for Osteoarthritis Treatment. (PubMed, ACS Appl Mater Interfaces) - "Notably, these therapeutic effects were achieved at a low dosage and few injection frequencies. In summary, we developed a nanodrug that offers a potent and clinically translatable strategy for OA therapy by targeting joint inflammation."

Journal • Immunology • Inflammation • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology • IL1B

Varespladib Alleviates Colonic Inflammation Induced by High-Fat Diet via Downregulating the TGF-β/Smad Pathway and AA Pathway by Inhibiting sPLA2. (PubMed, J Gastroenterol Hepatol) - "Short-term HFD induced intestinal inflammation. These disorders are mainly triggered by sPLA2 upregulation, resulting in activation of the arachidonic acid and TGF-β/smad pathways. Varespladib has significant therapeutic potential for alleviating HFD-induced colonic inflammation in mice."

Journal • Fibrosis • Immunology • Inflammation • Inflammatory Bowel Disease • Obesity • TGFB1

In vitro inhibition of snake venom toxins by varespladib, marimastat, nafamostat and dimercaprol. (PubMed, Toxicon) - "Nafamostat proved to be an inhibitor of snake venom serine protease (svSP) in B. arietans (IC50 = 3.72 μM), B. gabonica (IC50 = 3.80 μM) and Causus rhombeatus (IC50 = 0.261 μM). These data demonstrate that SMTs are effective inhibitors of the relevant enzymes in several snake species and support the proposal that SMTs could be developed for therapeutic intervention in snakebite envenoming."

Journal • Preclinical

Phospholipase A2 inhibitor may shorten the duration of clinical signs in the treatment of neurotoxicity caused by eastern coral snake (Micrurus fulvius) envenomation in 3 dogs. (PubMed, J Am Vet Med Assoc) - "No adverse effects were attributed to varespladib or antivenom administration. Varespladib may have a role in shortening the duration of the clinical signs of dogs envenomated by coral snakes and may reduce the need for mechanical ventilation in affected dogs."

Journal

Early anti-inflammatory therapy in acute myocardial infarction: A network meta-analysis of timing-dependent effects in 23 randomized trials and 28,220 patients. (PubMed, Atherosclerosis) - "This network meta-analysis demonstrates that anti-inflammatory therapy improves outcomes in AMI only when initiated early. Colchicine and anakinra were the only effective agents, highlighting a narrow therapeutic window and supporting a time-sensitive approach to inflammation-targeted treatment in AMI."

Journal • Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure • Infectious Disease • Inflammation • Myocardial Infarction • IL1B

Sex and dietary ALA and DHA effects on rat heart phospholipase A2 activity mediating fatty acid release and oxylipin formation have cardiovascular implications. (PubMed, Prostaglandins Leukot Essent Fatty Acids) - "Therefore, male and female Sprague-Dawley rats were provided diets with 1.3 % α-linolenic acid (ALA) or docosahexaenoic acid (DHA) for 6 weeks, and heart homogenates were incubated with inhibitors for secreted (s)PLA2 (Varespladib) or calcium-independent (i)PLA2 (methyl arachidonyl fluorophosphonate)...Interestingly, the sex effect on cyclooxygenase ARA oxylipins was attenuated with dietary DHA. These findings provide further rationale for the simultaneous measurement of PUFA and oxylipins since they are not always congruent, and shed new light on diet and sex effects on PLA2 types in cardiovascular oxylipin biology."

Journal • Preclinical • Cardiovascular

An Experimental Model of Acute Pulmonary Damage Induced by the Phospholipase A2-Rich Venom of the Snake Pseudechis papuanus. (PubMed, Toxins (Basel)) - "These effects were abrogated by incubating the venom with the PLA2 inhibitor varespladib, indicating that this hydrolytic enzyme is responsible for these alterations...Based on these findings, it is proposed that the rapid pathological effect of this venom in the lungs is mediated by (a) the direct cytotoxicity of venom PLA2 on cells of the capillary-alveolar barrier, (b) the degradation of surfactant factor by PLA2, (c) the deleterious action of nitric oxide in pulmonary tissue, and (d) the cytotoxic action of free hemoglobin that accumulates in the lungs as a consequence of venom-induced intravascular hemolysis. Our findings offer clues on the mechanisms of pathophysiological alterations induced by PLA2s in a variety of pulmonary diseases, including acute respiratory distress syndrome (ARDS)."

Journal • Acute Respiratory Distress Syndrome • Hematological Disorders • Oncology • Pulmonary Disease • Respiratory Diseases • TNFA

Optimizing Anti-Snake Venom Strategies for Hemotoxic Envenomation in Northern India: Clinical Outcomes and Regional Challenge. (PubMed, Cureus) - "It also explores emerging alternatives like Varespladib and monoclonal antivenoms...It concludes that standardizing ASV treatment based on regional evidence, enhancing healthcare capacity, and integrating public health education are essential to improving outcomes. The findings support the need for locally tailored, patient-centric treatment protocols and stronger public health systems to mitigate snakebite-related burdens."

Clinical data • Journal • Review

Preclinical evaluation of small molecule inhibitors as early intervention therapeutics against Russell's viper envenoming in India. (PubMed, Commun Med (Lond)) - "Our findings support the potential use of SMIs as effective, affordable, and accessible future therapies for treating bites from the world's most medically important snake species."

Journal • Preclinical

Phospholipase A2 Group IIA activates Indoleamine 2,3-dioxygenase 1 to drive the progression of pulmonary fibrosis. (PubMed, Free Radic Biol Med) - "In this study, we characterized the critical role of PLA2G2A in pulmonary fibrosis (PF) in both human patients and bleomycin (BLM)-induced PF mouse models...For therapeutic strategy, we administered Varespladib (a PLA2G2A inhibitor) and Indoximod (the selective IDO1 inhibitor) to the animals, both of which were found to mediate the progression of PF. Our findings suggest that PLA2G2A plays a central role in pro-fibrotic processes by modulating epithelial cells and fibroblasts, thereby promoting extracellular matrix production. Given its involvement in PF pathogenesis, PLA2G2A may serve as a potential therapeutic target for PF, with PLA2G2A inhibitors offering a promising strategy for clinical treatment."

IO biomarker • Journal • Fibrosis • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • IDO1 • NLRP3 • PLA2G2A • STING

Varespladib attenuates Naja atra-induced acute liver injury via reversing Nrf2 signaling-mediated ferroptosis and mitochondrial dysfunction. (PubMed, Redox Rep) - "Treatment with varespladib effectively reversed these pathological events by inhibiting SVPLA2 activity. Varespladib shows strong therapeutic potential for N. atra envenomation by targeting SVPLA2. Nrf2 was identified as a direct toxic target of SVPLA2, and Nrf2-mediated ferroptosis and mitochondrial dysfunction were key mechanisms underlying SVPLA2-induced hepatic injury."

Journal • Hepatology • Liver Failure • Metabolic Disorders

Snake venom protection by a cocktail of varespladib and broadly neutralizing human antibodies. (PubMed, Cell) - "We combined and tested these antibodies and the phospholipase inhibitor varespladib. A 3-component cocktail rescued animals from whole-venom challenge of all species in a 19-member WHO Category 1 and Category 2 elapid diversity set, with complete protection against most snakes observed."

Journal

Electrical Cell Impedance Sensing (ECIS): Feasibility of a Novel In Vitro Approach to Studying Venom Toxicity and Potential Therapeutics. (PubMed, Toxins (Basel)) - "Herein, we tested the use of a wound-healing study technique known as Electric Cell-Substrate Impedance Sensing (ECIS) to assess populations of cultured cells exposed to venom with or without sPLA2 and/or metalloprotease inhibitors (varespladib and marimastat, respectively)...Importantly, this approach is both quantitative and has the potential of reducing animal use and suffering during the evaluation of potential therapeutics. To further evaluate the potential of this method, rescue studies should be performed."

Journal • Preclinical • Hematological Disorders

In silico approach to screen anti-inflammatory phytochemicals: targeting cytosolic phospholipase A2 and phospholipase C. (PubMed, J Biomol Struct Dyn) - "However, the reference molecule Varespladib was observed to be interacted strongly with cPLA2 and feebly with the PLC. This is the first report on the strong efficacy of p-Coumaric acid against cPLA2."

Journal • Infectious Disease • Oncology • Peptic Ulcer

Broad-spectrum Rapid Antidote: Varespladib IV to Oral Trial for Snakebite (BRAVIO) (clinicaltrials.gov) - P2 | N=140 | Completed | Sponsor: Ophirex, Inc. | Recruiting ➔ Completed | Trial completion date: Jul 2025 ➔ Feb 2025 | Trial primary completion date: Mar 2025 ➔ Nov 2024

Trial completion • Trial completion date • Trial primary completion date

Feasibility study: Varespladib protects CD-1 mice from lethal doses of whole bee (Apis mellifera) venom. (PubMed, Toxicon X) - "Survival in these animals despite poor in vitro sPLA2 inhibition suggests that suppression of the host sPLA2 response itself might play a role in the treatment of venom toxicity using an enzyme inhibitor rather than antivenom antibodies. Varespladib could be a useful tool for dissecting fundamental interactions between exogenous toxins and their corresponding endogenous counterparts."

Journal • Preclinical • Hematological Disorders • Immunology • Renal Disease

Elucidating on the Quaternary Structure of Viper Venom Phospholipase A2 Enzymes in Aqueous Solution. (PubMed, Biochimie) - "Small-molecule inhibitors that act as snakebite antidotes, such as varespladib, are currently in clinical trials...Recognizing snakebite envenoming as a neglected tropical disease has driven the search for efficient, affordable alternatives to the current antivenoms. Therefore, understanding the main drug targets within snake venom is crucial to this achievement."

Journal