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

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."

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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."

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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."

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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."

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

Trial completion date • Trial primary completion date

Exploring the Inhibitory Potential of Phytochemicals from Vernonia glaberrima leaves against Snake Venom Toxins through Computational Simulation and Experimental Validation. (PubMed, Toxicon) - "Furthermore, the compounds were able to bind to the active site of PLA2 enzyme with high affinity (-7.7 to -6.3 kcal/mol); the standard ligand, Varespladib had a docking score of -6.9 kcal/mol and they exhibited favorable drug-likeness and pharmacokinetic properties and according to toxicity predictions, the two compounds are toxic. In conclusion, the leaf of V. glaberrima contains phytoconstituents with antisnake activity and thus, validates the hypothesis that, the phytoconstituents of V. glaberrima leaves has antisnake venom activity against N. nigricollis venom and thus, should be studied further for the development as antisnake venom agents."

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Anticoagulant activity in Australasian elapid snake venoms and neutralisation with antivenom and varespladib. (PubMed, Toxicon) - "We found anticoagulant activity to be present in six genera of Australasian snakes at low concentrations, which can be completely neutralised by both antivenom and varespladib. Anticoagulant activity in Australian elapid venoms was associated with species possessing high PLA2 activity without procoagulant snake venom serine proteases."

Journal • Genetic Disorders • Hematological Disorders • Metabolic Disorders

Inhibiting arachidonic acid generation mitigates aging-induced hyperinsulinemia and insulin resistance in mice. (PubMed, Clin Nutr) - "Collectively, our findings uncover that arachidonic acid serves as a metabolic hub in Chinese elderly population. Our results also suggest that arachidonic acid plays a fundamental role in regulating β-cell function during aging and point to a novel therapy for aging-associated diabetes."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib. (PubMed, Proc Natl Acad Sci U S A) - "We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a therapeutic strategy that may effectively prevent life-changing morbidity caused by snakebite in rural Africa."

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Development of a membrane-disruption assay using phospholipid vesicles as a proxy for the detection of cellular membrane degradation. (PubMed, Toxicon X) - "The assay proved to be suitable for studying phospholipid vesicle degradation of crude venoms and was also tested for its applicability for neutralisation studies of varespladib, which is a PLA2 inhibitor...We successfully identified various toxins in the venoms of C. rhodostoma and N. mossambica, which are likely to be involved in the observed vesicle-degrading effect. This indicates that the assay can be used for screening the membrane degrading activity of both crude and fractionated venoms as well as for neutralisation studies."

Journal • Ophthalmology • Pain

Varespladib mitigates acute liver injury via suppression of excessive mitophagy on Naja atra envenomed mice by inhibiting PLA2. (PubMed, Toxicon) - "The results showed that an N. atra bite induced ALI by activating mitophagy and inducing inflammation and that varespladib had a protective effect. Collectively, these results showed the pathological mechanism of ALI caused by N. atra bite and revealed the protective effect of varespladib."

Journal • Preclinical • Hepatology • Inflammation • Liver Failure

A Comparison of the Efficacy of Antivenoms and Varespladib against the In Vitro Pre-Synaptic Neurotoxicity of Thai and Javanese Russell's Viper (Daboia spp.) Venoms. (PubMed, Toxins (Basel)) - "The efficacy of Thai D. siamensis monovalent antivenom in reversing pre-synaptic neurotoxicity was significantly enhanced by its co-administration with Varespladib. Further work is required to establish the efficacy of Varespladib as a primary or adjunct therapy in human envenoming."

Journal • Preclinical

Wasp venom-induced acute kidney injury: current progress and prospects. (PubMed, Ren Fail) - "In addition, studies on cilastatin and varespladib for wasp venom-induced AKI treatment have shown their potential as therapeutic agents. This review summarizes the available evidence on the mechanisms and treatment of wasp venom-induced AKI, with a particular focus on the role of inflammatory responses and potential targets for therapeutic drugs, and, therefore, aiming to support the development of clinical treatment against wasp venom-induced AKI."

Journal • Review • Acute Kidney Injury • Hematological Disorders • Inflammation • Nephrology • Renal Disease • MB

Differential effects of the venoms of Russell's viper and Indian cobra on human myoblasts. (PubMed, Sci Rep) - "Cobra venom-induced atrophy could not be reversed by small molecule inhibitors such as varespladib (a phospholipase A2 inhibitor) and prinomastat (a metalloprotease inhibitor), and soluble activin type IIb receptor (a molecule used to promote regeneration of skeletal muscle), although the antivenom (raised against the Indian 'Big Four' snakes) has attenuated the effects...This study demonstrates key steps in the muscle regeneration process that are affected by both Indian Russell's viper and cobra venoms and offers insights into the potential causes of clinical features displayed in envenomed victims. Further research is required to investigate the molecular mechanisms of venom-induced myotoxicity under in vivo settings and develop better therapies for snakebite-induced muscle damage."

Journal • Muscular Atrophy

Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform. (PubMed, Front Pharmacol) - "The phospholipases A2 (PLA) are one of the main pathogenic toxin classes found in medically important viper and elapid snake venoms, yet varespladib, a drug originally developed for the treatment of acute coronary syndrome, remains the only PLA inhibitor shown to effectively neutralise venom toxicity in vitro and in vivo, resulting in an extremely limited drug portfolio...We further explore the broad-spectrum inhibitory potential and efficacy of the resulting top hits against a range of medically important snake venoms and demonstrate the utility of our method in determining drug ECs. Collectively, our findings support the future application of this method to fully explore the chemical space to discover novel PLA-inhibiting drugs of value for preventing severe pathology caused by snakebite envenoming."

Journal • Acute Coronary Syndrome • Cardiovascular

Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms. (PubMed, Nat Commun) - "Thereafter, using preclinical mouse models of dermonecrosis, we demonstrate that the dual therapeutic combinations of DMPS or marimastat with varespladib significantly inhibit the dermonecrotic activity of geographically distinct and medically important snake venoms, even when the drug combinations are delivered one hour after envenoming. These findings strongly support the future translation of repurposed drug combinations as broad-spectrum therapeutics for preventing morbidity caused by snakebite."

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