- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: Exploring the Inhibitory Potential of Phytochemicals from Vernonia glaberrima leaves against Snake Venom Toxins through Computational Simulation and Experimental Validation. (Pubmed Central) - Jul 28, 2024
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.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Trial completion date, Trial primary completion date: Broad-spectrum Rapid Antidote: Varespladib IV to Oral Trial for Snakebite (BRAVIO) (clinicaltrials.gov) - Jul 17, 2024
P2, N=140, Recruiting,
Anticoagulant activity in Australian elapid venoms was associated with species possessing high PLA2 activity without procoagulant snake venom serine proteases. Trial completion date: Dec 2024 --> Jul 2025 | Trial primary completion date: Dec 2024 --> Mar 2025
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: Development of a membrane-disruption assay using phospholipid vesicles as a proxy for the detection of cellular membrane degradation. (Pubmed Central) - Apr 18, 2024
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.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: Optimizing drug discovery for snakebite envenoming via a high-throughput phospholipase A2 screening platform. (Pubmed Central) - Jan 26, 2024
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.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: Repurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms. (Pubmed Central) - Dec 14, 2023
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.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Review, Journal: Unraveling snake venom phospholipase A: an overview of its structure, pharmacology, and inhibitors. (Pubmed Central) - Nov 22, 2023
Research in recent years has shown that various small molecules, such as varespladib and methyl varespladib, effectively inhibit the PLA toxin. In the present article, we have overviewed the knowledge of snake venom phospholipase A, its classification, and the mechanism involved in the pathophysiology of cytotoxicity, myonecrosis, anticoagulation, and inflammation clinical application and inhibitors of SvPLA, along with the list of studies carried out to evaluate the potency of small molecules like varespladib and secondary metabolites from the traditional medicine for their anti-PLA effect.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Trial completion date, Trial primary completion date: Broad-spectrum Rapid Antidote: Varespladib IV to Oral Trial for Snakebite (BRAVIO) (clinicaltrials.gov) - Sep 25, 2023
P2, N=140, Recruiting,
Further clinical study as initial therapy and as potential method of rescue from some types of antivenom-resistant envenomings are supported by these data. Trial completion date: Aug 2024 --> Nov 2024 | Trial primary completion date: Jul 2024 --> Oct 2024
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Trial completion, Trial completion date, Trial primary completion date: BRAVO: Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite (clinicaltrials.gov) - Jun 12, 2023
P2, N=96, Completed,
Trial completion date: Aug 2024 --> Nov 2024 | Trial primary completion date: Jul 2024 --> Oct 2024 Recruiting --> Completed | Trial completion date: Mar 2023 --> Jun 2023 | Trial primary completion date: Feb 2023 --> Jun 2023
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Enrollment open, Trial completion date, Trial initiation date, Trial primary completion date: Broad-spectrum Rapid Antidote: Varespladib IV to Oral Trial for Snakebite (BRAVIO) (clinicaltrials.gov) - Jun 8, 2023
P2, N=110, Recruiting,
Recruiting --> Completed | Trial completion date: Mar 2023 --> Jun 2023 | Trial primary completion date: Feb 2023 --> Jun 2023 Not yet recruiting --> Recruiting | Trial completion date: Apr 2024 --> Aug 2024 | Initiation date: Mar 2023 --> May 2023 | Trial primary completion date: Mar 2024 --> Jul 2024
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: In Silico Evaluation of Quercetin Methylated Derivatives on the Interaction with Secretory Phospholipases A2 from Crotalus durissus terrificus and Bothrops jararacussu. (Pubmed Central) - Apr 28, 2023
Results reveal that analogue and inhibitors, Varespladib (Var) and p-bromophenacyl bromide (BPB), guided quercetins derivatives analysis, revealing that Leu2, Phe5, Tyr28, glycine in the calcium-binding loop, His48, Asp49 of BthTX-II and Cdtspla2 were the main residues to be inhibited...However, strong interactions in the C-terminal region, highlighting His120, seem to be crucial to decreasing contacts with phospholipid and BthTX-II. Hence, quercetin derivatives anchor differently with each toxin and further in vitro and in vivo studies are essential to elucidate these data.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Preclinical, Journal: Phospholipase A enzymes differently impact PUFA release and oxylipin formation ex vivo in rat hearts. (Pubmed Central) - Apr 4, 2023
Sprague-Dawley rat heart homogenates were incubated without or with varespladib (VAR), methyl arachidonyl fluorophosphonate (MAFP) or EDTA...In conclusion, sPLA enzymes lead to the formation of DHA oxylipins, while iPLA is likely responsible for the formation of most other oxylipins in healthy rat hearts. Oxylipin formation cannot be implied from PUFA release, thus, both should be evaluated in PLA activity studies.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib. (Pubmed Central) - Mar 24, 2023
However, an additional varespladib binds to a particular site that is related to muscle cell disruption by these toxins (MDiS region). The present results further advance the characterization of the molecular interactions of varespladib with PLA-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA and PLA-like toxins.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Preclinical, Journal: In Vitro Efficacy of Antivenom and Varespladib in Neutralising Chinese Russell's Viper (Daboia siamensis) Venom Toxicity. (Pubmed Central) - Jan 21, 2023
The addition of the combination of Varespladib and antivenom 60 min after venom failed to produce further improvements than Varespladib alone. This demonstrates that the window of time in which antivenom remains effective is relatively short compared to Varespladib and small-molecule inhibitors may be effective in abrogating some activities of Chinese D. siamensis venom.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Trial completion date, Trial termination, Trial primary completion date: STAIRS: Study of Varespladib in Patients Hospitalized With Severe COVID-19 (clinicaltrials.gov) - Dec 16, 2022
P2, N=18, Terminated,
This demonstrates that the window of time in which antivenom remains effective is relatively short compared to Varespladib and small-molecule inhibitors may be effective in abrogating some activities of Chinese D. siamensis venom. Trial completion date: Jun 2023 --> Nov 2022 | Active, not recruiting --> Terminated | Trial primary completion date: Oct 2022 --> Feb 2022; Part 2 of the study was paused on 03-May-2022 due to slow enrollment following low infection rates and hospitalizations of patients with severe COVID-19, and did not recommence prior to study closure (early termination) on 22-Nov-2022.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Preclinical, Review, Journal: Varespladib in the Treatment of Snakebite Envenoming: Development History and Preclinical Evidence Supporting Advancement to Clinical Trials in Patients Bitten by Venomous Snakes. (Pubmed Central) - Nov 25, 2022
Since 2016, more than 30 publications describing the structure, function, and efficacy of varespladib have directly addressed its potential for the treatment of snakebite. This review summarizes preclinical findings and outlines the scientific support, the potential limitations, and the next steps in the development of varespladib's use as a snakebite treatment, which is now in Phase 2 human clinical trials in the United States and India.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
A novel in-vitro model replicating the pathophysiology of human visceral fat necrosis during acute pancreatitis (Coastal 1-5) - Nov 7, 2022 - Abstract #APAPancreatic2022APA_Pancreatic_224;
The novel experimental setup using 3 T3-L1 adipocytes, PPL replicates critical features of pancreatic fat necrosis during human acute pancreatitis. This shows an essential and synergistic role of PLA2 and PNLIP in mediating fat necrosis by allowing pharmacologic inhibition and recombinant proteins to understand the pathophysiology and outcomes resulting from fat necrosis.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: STAIRS: Study of Varespladib in Patients Hospitalized With Severe COVID-19 (clinicaltrials.gov) - Sep 21, 2022
P2, N=18, Active, not recruiting,
This shows an essential and synergistic role of PLA2 and PNLIP in mediating fat necrosis by allowing pharmacologic inhibition and recombinant proteins to understand the pathophysiology and outcomes resulting from fat necrosis. Recruiting --> Active, not recruiting | N=90 --> 18 | Trial completion date: Dec 2022 --> Jun 2023 | Trial primary completion date: Jul 2022 --> Oct 2022
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Trial completion date, Trial primary completion date: BRAVO: Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite (clinicaltrials.gov) - Aug 22, 2022
P2, N=110, Recruiting,
Recruiting --> Active, not recruiting | N=90 --> 18 | Trial completion date: Dec 2022 --> Jun 2023 | Trial primary completion date: Jul 2022 --> Oct 2022 Trial completion date: Oct 2022 --> Jan 2023 | Trial primary completion date: Sep 2022 --> Dec 2022
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: The relative efficacy of chemically diverse small-molecule enzyme-inhibitors against anticoagulant activities of Black Snake (Pseudechis spp.) venoms. (Pubmed Central) - Aug 11, 2022
Utilising validated coagulation assays, our study assessed the efficacy of two chemically different small molecule inhibitors, a phospholipase A inhibitor (varespladib) and a metalloproteinase inhibitor (prinomastat), in vitro neutralisation of the anticoagulant prothrombinase-inhibiting activity of venom from seven species within the Pseudechis genus (P...These results build upon recent literature indicating that metalloproteinase inhibitors have cross-neutralising potential towards snake venom phospholipase A toxins, but with higher degrees of variability that PLA2-specific inhibitors. An important caveat is that these are in vitro tests and while suggestive of potential clinical utility, in vivo animal testing and clinical trials are required as future work.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: Efficacy and Limitations of Chemically Diverse Small-Molecule Enzyme-Inhibitors against the Synergistic Coagulotoxic Activities of Bitis Viper Venoms. (Pubmed Central) - Mar 24, 2022
Utilising well-validated coagulation assays measuring time until clot formation, this study addresses the in vitro efficacy of three small molecule enzyme inhibitors (marimastat, prinomastat and varespladib) in neutralising these aforementioned activities...Our results highlight the complex nature of snake venoms, for which single-compound treatments will not be universally effective, but combinations might prove highly effective. Despite the limitations of these inhibitors with regards to in vitro kallikrein enzyme pseudo-procoagulant venom activity, our results further support the growing body of literature indicating the potential use of small molecule inhibitors to enhance first-aid treatment of snakebite envenoming, particularly in cases where hospital and thus antivenom treatment is either unavailable or far away.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Trial completion date, Trial primary completion date: STAIRS: Study of Varespladib in Patients Hospitalized With Severe COVID-19 (clinicaltrials.gov) - Mar 23, 2022
P2, N=90, Recruiting,
Despite the limitations of these inhibitors with regards to in vitro kallikrein enzyme pseudo-procoagulant venom activity, our results further support the growing body of literature indicating the potential use of small molecule inhibitors to enhance first-aid treatment of snakebite envenoming, particularly in cases where hospital and thus antivenom treatment is either unavailable or far away. Trial completion date: Jan 2022 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Jul 2022
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Trial completion date, Trial primary completion date: BRAVO: Broad-spectrum Rapid Antidote: Varespladib Oral for Snakebite (clinicaltrials.gov) - Feb 10, 2022
P2, N=110, Recruiting,
The findings suggest varespladib could be repurposed as an emergency drug for rescue from or, if given early enough, prevention of the acute, neurotoxic envenoming syndromes caused by various major krait species in Asia. Trial completion date: Feb 2022 --> Oct 2022 | Trial primary completion date: Jan 2022 --> Sep 2022
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Clinical, Journal: The Relative Efficacy of Chemically Diverse Small-Molecule Enzyme-Inhibitors Against Anticoagulant Activities of African Spitting Cobra (Naja Species) Venoms. (Pubmed Central) - Feb 5, 2022
Previous work demonstrated that the enzyme-inhibitor varespladib was able to neutralize this toxic action for N. mossambica, N. nigricincta, N. nigricollis, and N. pallida venoms...In addition we showed that the metalloprotease-inhibitor marimastat was also able to cross-neutralize PLA but less effectively than prinomastat. Due to logistical (cold-chain requirement) and efficacy (cross-reactivity across snake species) limitations of traditional antivenoms, particularly in developing countries where snakebite is most common, these small molecule inhibitors (SMIs) might hold great promise as initial, field-based, treatments for snakebite envenoming as well as addressing fundamental limitations of antivenom in the clinical setting where certain toxin effects are unneutralized.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Biomarker, Preclinical, Journal: In vivo treatment with varespladib, a phospholipase A inhibitor, prevents the peripheral neurotoxicity and systemic disorders induced by Micrurus corallinus (coral snake) venom in rats. (Pubmed Central) - Feb 5, 2022
In conclusion, VPL shows to be effective at preventing the neurotoxic, nephrotoxic, and inflammatory activities of M. corallinus venom. In addition, VPL acts synergistically with antivenom to prevent a number of systemic effects caused by M. corallinus venom.
- |||||||||| varespladib (A-002) / Anthera Pharma, Ophirex
Journal: Quantum Biochemical Investigation of Lys49-PLA from Bothrops moojeni. (Pubmed Central) - Jan 27, 2022
Furthermore, we have identified the role played by the amino acids LYS0069, LYS0049, LEU0005, ILE0009, CYS0029, GLY0030, HIS0048, PRO0018, ALA0019, CYS0045, TYR0052, TYR0022, PRO0125*, and PHE0126* (LYS0069, LYS0049, GLY0032, LEU0002, and LEU0005) in the VRD↔Lys49-PLA (AIN↔Lys49-PLA) complex. Our simulations are a valuable tool to support the big challenge for neutralizing the damages in victims of snakebites.
- |||||||||| Actemra IV (tocilizumab) / Roche, JW Pharma
Review, Journal: The role and transformative potential of IL-19 in atherosclerosis. (Pubmed Central) - Dec 16, 2021
Several other drugs have also been investigated in clinical trials as anti-inflammatory agents; the development of some of these agents has been terminated (canakinumab, darapladib, varespladib, losmapimod, atreleuton, setileuton, PF-04191834, veliflapon, and methotrexate), but others remain in development (ziltivekimab, tocilizumab, Somalix, IFM-2427, anakinra, mesenchymal stem cells (MSCs), colchicine, everolimus, allopurinol, and montelukast)...We propose that IL-19 is a promising biomarker and target for the diagnosis and treatment of atherosclerosis. This review considers the role and mechanism of action of IL-19 in atherosclerosis and discusses whether IL-19 is a potential therapeutic target for this condition.
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