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

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

A genus-wide study on venom proteome variation and phospholipase A2 inhibition in Asian lance-headed pit vipers (genus: Trimeresurus). (PubMed, Comp Biochem Physiol C Toxicol Pharmacol) - "The commercial mono-specific antivenom effectively neutralized the venoms' procoagulant and hemorrhagic effects but failed to inhibit the PLA2 activities. Instead, the PLA2 activities of all venoms were effectively inhibited by the small molecule inhibitor varespladib, suggesting its potential to be repurposed as a highly potent adjuvant therapeutic in snakebite envenoming."

Journal • Hematological Disorders

In vitro anticoagulant effects of Bungarus venoms on human plasma which are effectively neutralized by the PLA2-inhibitor varespladib. (PubMed, Toxicon) - "The anticoagulant effects of both B. flaviceps and B. caeruleus were nullified by varespladib, a phospholipase A2 (PLA2) inhibitor, revealing the toxin class involved. These results uncover previously unrecognized and unexplored anticoagulant effects of Bungarus venoms."

Journal • Preclinical

High expression of PLA2G2A in fibroblasts plays a crucial role in the early progression of carotid atherosclerosis. (PubMed, J Transl Med) - "Our study discovered and validated that PLA2G2A is highly expressed by vascular fibroblasts and promotes plaque progression through the activation of macrophage complement and coagulation cascade pathways in the early-stage of CA."

Journal • Atherosclerosis • Cardiovascular • Dyslipidemia • Inflammation • PLA2G2A

Breaking muscle: neurotoxic and myotoxic effects of Central American snake venoms and the relative efficacies of antivenom and varespladib. (PubMed, BMC Biol) - "This study characterises the myotoxic and neurotoxic venom activity, as well as neutralisation of venom effects from the Atropoides, Cerrophidion, and Metlapilcoatlus clade of American crotalids. Our findings contribute significant clinical and evolutionary knowledge to a clade of poorly researched snakes. In addition, these results provide a platform for future research into the reciprocal interaction between ecological niche specialisation and venom evolution, as well as highlighting the need to test purified toxins to accurately evaluate the potential effects observed in these venoms."

Journal

Oral varespladib for the treatment of snakebite envenoming in India and the USA (BRAVO): a phase II randomised clinical trial. (PubMed, BMJ Glob Health) - "For emergency department treatment of snakebites, the addition of varespladib to antivenom did not find evidence of difference for the primary outcome based on the SSS. A potentially promising signal of benefit was observed in patients initiating treatment within 5 hours of snakebite."

Clinical • Journal • P2 data

Isolation and Pharmacological Characterisation of Pre-Synaptic Neurotoxins from Thai and Javanese Russell's Viper (Daboia siamensis) Venoms. (PubMed, Toxins (Basel)) - "Additionally, the neurotoxicity produced by a combination of the two fractions was partially reversed by the addition of Varespladib (100-300 nM) 60 min after the fractions. The present study demonstrates that the in vitro skeletal muscle effects of Thai and Javanese D. siamensis venoms are primarily due to key PLA2 toxins in each venom."

Journal