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

Effects of Phospholipase A2 and Metalloproteinase Inhibitors on Skeletal Muscle Regeneration After Myonecrosis Induced by the Venom of Bothrops asper: An Initial Assessment in Mice. (PubMed, Toxins (Basel)) - "Using a mouse model of myonecrosis and regeneration, we evaluated the effects of Varespladib (a phospholipase A2 inhibitor) or Marimastat (a metalloproteinase inhibitor) on muscle regeneration when administered intravenously 24 h after the onset of myonecrosis, i.e., after muscle damage has occurred...Marimastat, or a combination of both inhibitors, increased the number and diameter of regenerating muscle fibers and reduced tissue fibrosis compared to tissues from mice receiving only venom, as judged by qualitative and quantitative histological assessment. These initial results underscore the deleterious role of traces of venom components, especially metalloproteinases, in damaged muscles during muscle regeneration."

Journal • Preclinical • Fibrosis • Immunology

Adjunctive Varespladib after antivenom administration for snakebite: A phase II randomized clinical trial. (PubMed, PLoS Negl Trop Dis) - P2 | "In this trial in which varespladib was initiated on average 7 hours after snakebite and several hours after antivenom, late adjunctive varespladib did not meet the primary endpoint. Interpretation of these results is limited by heterogeneity in the snake species responsible for envenoming and the associated differences in venom composition, clinical manifestations, and antivenom treatments."

Clinical • Journal • P2 data

Why does local edema persist? Immunological mismatch between phospholipase A2 potency and antivenom affinity in Protobothrops mucrosquamatus envenomation. (PubMed, PLoS Negl Trop Dis) - "Persistent localized edema arises from an immunological mismatch in which FHAV recognizes primarily high-molecular-weight immunogens instead of the primary edematogenic driver, PLA2. Current clinical management necessitates increasing FHAV dosages to compensate for low specific affinity through increased total antibody volume. These findings highlight that robust prospective multicenter trials are urgently needed to transition from empirical dosing to standardized, potency-aligned FHAV protocols, potentially incorporating multimodal therapeutic cocktails to achieve comprehensive neutralization."

Journal • Retrospective data • Hematological Disorders

Varespladib for snakebite envenoming. (PubMed, Expert Opin Investig Drugs) - "Clinical evidence from these studies supports further evaluation of varespladib as an in-hospital treatment administered, with encouraging signals from Agkistrodon contortrix (copperhead), Micrurus fulvius (eastern coral snake), and Bungarus spp (krait). Additional studies may provide insight into the benefit of varespladib as a time-of-bite treatment in specific regions."

Journal • Review

Mechanism of theHIF-1α/PLA2g2a/LPC pathway in epicardial adipose tissue in cardiac fibrosis following myocardial ischemia-reperfusion injury (ESC 2026) - "In rat I/R models, EAT resection, Varespladib intervention, adipose-specific PLA2g2a knockout and EAT-targeted HIF-1α inhibition were performed...Targeting this axis alleviates fibrosis and improves cardiac function. This study identifies EAT as an active pathogenic signal source and the HIF-1α/PLA2g2a/LPC axis as a novel target with good clinical translational potential for post-infarction anti-fibrotic therapy."

Cardiovascular • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • HIF1A • PLA2G2A

Naja atra SVPLA2 contributes to venom-induced AKI via HRAS palmitoylation-dependent PI3K-AKT inactivation. (PubMed, J Lipid Res) - "Although the SVPLA2 inhibitor varespladib shows great therapeutic promise, the underlying mechanisms remain incompletely understood...These findings highlight PI3K-AKT signaling and HK2 as potential therapeutic targets for N. atra-triggered AKI. Supplementary key words."

Journal • Acute Kidney Injury • Metabolic Disorders • Nephrology • Renal Disease • CCND1 • HRAS

Role of Regulated Cell Death Pathways in Snakebite Envenomation: Mechanisms, Crosstalk, and Therapeutic Opportunities. (PubMed, Int J Mol Sci) - "We further discuss the crosstalk between these RCD pathways and emerging therapeutic approaches targeting these mechanisms. Understanding these interconnected RCD pathways may facilitate the development of adjunct therapies that complement antivenom, reduce snakebite-induced morbidity, and improve clinical outcomes."

Journal • Review

Repurposed small molecule toxin inhibitors neutralise a diversity of venoms from the Neotropical viperid snake genus Bothrops. (PubMed, Elife) - "Despite variable toxin representation and bioactivity across this central and south American genus, we found that the lead inhibitors targeting metalloproteinases (marimastat and DMPS) and phospholipases (varespladib) demonstrated pan-species neutralisation in enzymatic assays, whilst nafamostat (serine protease inhibitor) had variable activity. The metalloproteinase inhibitors protected against the procoagulant and haemorrhagic effects of several venoms in phenotypic assays. Collectively these findings demonstrate that repurposed drugs may be of great value as early interventions for the treatment of bothropic envenoming in the Neotropics and thus provide a strong rationale for their progression into future preclinical and clinical evaluation for snakebite indication."

Journal

Non-targeted metabolomics reveals the metabolic atlas of macrophages remodeled by SVPLA2 in Naja atra venom. (PubMed, Toxicon) - "Using non-targeted metabolomics, combined with multivariate statistics and KEGG pathway enrichment, this study delineated the metabolic reprogramming of RAW 264.7 macrophages induced by SVPLA2 in N. atra venom and assessed the reversal effects of the specific inhibitor varespladib...KEGG analysis further confirmed the involvement of arachidonic acid metabolism, PPAR signaling, peroxisome, and pyrimidine metabolism pathways. This study expands the functional role of SVPLA2 from conventional membrane phospholipid hydrolysis to the regulation of the macrophage metabolic reprogramming associated with inflammatory, energy-related, and pyrimidine metabolic pathways, providing a new insight for understanding snake venom pathogenesis."

Journal

Comparison of the efficacy of varespladib and coral snake antivenom against the activities of the Amazon coral snake (Micrurus spixii) venom. (PubMed, Toxicon) - "Neostigmine, an anticholinesterase drug, showed only modest protection against lethality and neuromuscular blockade. These findings suggest that VPL could be a potential adjunct to conventional antivenom therapy in treating envenomation by M. spixii."

Journal

Turning Snake Venom To Therapy: Characterization Of Procoagulant Proteins for Human Bleeding Disorders (ISTH 2026) - "Snake venom-induced coagulation in human plasma was assessed with and without cofactors (calcium/phospholipids), essential coagulation factors (FV, FX, and FII), and inhibitors of venom phospholipases A2 (varespladib) or metalloproteases (marimastat)...Page 2 Table or Figure Upload (2) Spectrophotometric absorbance of substrate converted by venom-activated human factor X (FXa). DOI*10.1016/j.rpth.2026.105890"

Cardiovascular • Hematological Disorders

Hydrolysis and depletion of phosphatidylglycerol at peak murine acute lung injury. (PubMed, J Lipid Res) - "During peak ALI, a separate cohort of IT-LPS mice received IT-varespladib, an sPLA2 inhibitor, with surfactant outcomes analyzed 4 h later...Pharmacologic inhibition of sPLA2 at peak ALI improves PG content and surfactant function. Additional substudies to fully examine their relationships and mechanisms are warranted."

Journal • Preclinical • Acute Lung Injury • Acute Respiratory Distress Syndrome • Inflammation • Pneumonia • Pulmonary Disease • Respiratory Diseases

Lessons Learned from a Military-Biotechnology Partnership to Develop a Broad-Spectrum Small-Molecule Inhibitor for Snakebite Envenoming. (PubMed, Toxins (Basel)) - "This article describes the collaboration between Ophirex, a Public Benefit Corporation developing the oral secretory phospholipase A2 (sPLA2) inhibitor varespladib, and the United States military, which has identified a capability gap in snakebite treatment for forward-deployed personnel...From early proof-of-concept studies through regulatory pathway definition and advanced development, the Military-Ophirex partnership integrated operational requirements, regulatory planning, and iterative risk mitigation to advance manufacturing, nonclinical, and clinical development. This work provides both practical insights into complex drug development and a case study in how structured partnerships can carry innovation through translation in underfunded and operationally challenging conditions."

Journal • Licensing / partnership • Review

Naja atra SVPLA2 Aggravates Acute Kidney Injury Through Metabolic Reprogramming-Dependent Macrophage Polarization and Defective Efferocytosis. (PubMed, Toxins (Basel)) - "In vivo, AKI was induced in C57BL/6J mice by intraperitoneal administration of N. atra venom, followed by treatment with the SVPLA2 inhibitor varespladib...Pharmacological inhibition of SVPLA2 partially restored macrophage metabolic features and efferocytic capacity and was accompanied by attenuation of renal injury. Together, these findings support a model in which SVPLA2 exposure is associated with macrophage immunometabolic remodeling and impaired apoptotic cell clearance during venom-induced AKI."

Journal • Acute Kidney Injury • Nephrology • Renal Disease

Chinese cobra (Naja atra) SVPLA2 promotes muscle inflammation via RPL35A-mediated translational reprogramming. (PubMed, Commun Biol) - "Notably, AAV9-mediated RPL35A knockdown in the mouse gastrocnemius reduces inflammation and tissue injury, with combined p38 inhibition providing synergistic protection in vivo, and similar effects are observed in vitro. Taken together, this study reveals that SVPLA2 drives pathology via coordinated transcriptional and translational mechanisms, supports varespladib's therapeutic potential, and unveils a non-canonical pro-inflammatory role of RPL35A beyond its ribosomal function, which offers therapeutic possibilities for the treatment of other inflammatory diseases."

Journal • Inflammation • IL6 • PTBP1 • TNFA

The metalloproteinase inhibitor Marimastat improves skeletal muscle regeneration when administered intravenously after myonecrosis induced by the venom of Bothrops asper. (PubMed, bioRxiv) - "Using a mouse model of myonecrosis and regeneration, we evaluated the effects of Varespladib (a phospholipase A 2 inhibitor) or Marimastat (a metalloproteinase inhibitor) on muscle regeneration when administered intravenously 24 h after the onset of myonecrosis, i.e., after muscle damage has occurred...Results show that Marimastat, or a combination of both inhibitors, improved the extent of skeletal muscle regeneration and reduced the extent of tissue fibrosis when compared to tissue from mice receiving venom and no inhibitors, as judged by qualitative and quantitative histological assessment. Results underscore the deleterious role of traces of venom components in the damaged muscle during muscle regeneration and suggest that the administration of metalloproteinase inhibitors, or a combination of metalloproteinase and phospholipase A 2 inhibitors, even when muscle damage has developed, may be a therapeutic alternative for improving the extent of muscle regeneration."

Journal • Fibrosis • Immunology

Antivenom Therapy: History, Production, and Emerging Innovations. (PubMed, Wilderness Environ Med) - "Emerging agents such as varespladib and marimastat highlight the potential of targeted adjuncts to mitigate systemic and local effects of envenomation, whereas recombinant and engineered antibodies promise safer, more consistent, and more cost-effective solutions. Together these innovations aim to overcome long-standing barriers in antivenom development, offering renewed hope for effective, accessible, and equitable therapies. However, no single approach yet addresses all challenges, underscoring the need for continued multidisciplinary efforts to improve outcomes for envenomated patients worldwide."

Journal • Review • Immunology

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 ) - "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