Varespladib is an

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

of the IIa, V, and X

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

of secretory phospholipase A2 (sPLA2). The

molecule A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...

acts as an anti-inflammatory agent by disrupting the first step of the

arachidonic acid pathway Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

. From 2006 to 2012, varespladib was under active investigation by Anthera Pharmaceuticals as a potential therapy for several

inflammatory diseases Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants. The five cardinal signs are heat, pain, redness, swelling, and Functio laesa, loss of funct ...

, including

acute coronary syndrome Acute coronary syndrome (ACS) is a syndrome due to decreased blood flow in the coronary arteries such that part of the heart muscle is unable to function properly or dies. The most common symptom is centrally located pressure-like chest pain, ...

and

acute chest syndrome Acute chest syndrome is a vaso-occlusive crisis of the pulmonary vasculature commonly seen in people with sickle cell anemia. This condition commonly manifests with a new opacification of the lung(s) on a chest x-ray. Signs and symptoms The cris ...

. The trial was halted in March 2012 due to inadequate efficacy. The selective sPLA2 inhibitor varespladib (IC50 value 0.009 μM in chromogenic assay, mole fraction 7.3X10-6) was studied in the VISTA-16 randomized clinical trial (clinicaltrials.gov Identifier: NCT01130246) and the results were published in 2014. The sPLA2 inhibition by varespladib in this setting seemed to be potentially harmful, and thus not a useful strategy for reducing adverse cardiovascular outcomes from acute coronary syndrome. Since 2016, scientific research has focused on the use of Varespladib as an inhibitor of snake venom toxins using various types of in vitro and in vivo models. Varespladib showed a significant inhibitory effect to snake venom PLA₂ which makes it a potential first-line drug candidate in snakebite envenomation therapy. In 2019, the U.S. Food and Drug Administration (FDA) granted varespladib orphan drug status for its potential to treat snakebite.

History

Varespladib methyl was originally developed jointly by

Eli Lilly and Company Eli Lilly and Company, Trade name, doing business as Lilly, is an American multinational Medication, pharmaceutical company headquartered in Indianapolis, Indiana, with offices in 18 countries. Its products are sold in approximately 125 count ...

and Shionogi & Co., Ltd., and was acquired by Anthera Pharmaceuticals in 2006. A Phase II study demonstrated selective sPLA2 inhibition as well as statistically significant anti-inflammatory responses and reductions in LDL cholesterol levels. Two other Phase II trials, conducted in patients with coronary artery disease, found significant decreases in sPLA2 and LDL cholesterol levels, as well as C-reactive protein (CRP) and other inflammatory

biomarkers In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

. Varespladib methyl has also been shown to further reduce LDL and inflammatory biomarker levels when administered in conjunction with a cholesterol lowering

statin Statins (or HMG-CoA reductase inhibitors) are a class of medications that lower cholesterol. They are prescribed typically to people who are at high risk of cardiovascular disease. Low-density lipoprotein (LDL) carriers of cholesterol play ...

therapy. In 2010, a Phase III study entitled VISTA-16 was initiated to evaluate the safety and efficacy of short-term treatment with varespladib methyl in subjects with ACS. The trial was halted in March 2012 due to insufficient efficacy. On November 18, 2013, an excess of myocardial infarctions, and of the composite endpoint of cardiovascular mortality, myocardial infarctions and stroke in the VISTA-16 study were reported. First report on its efficacy as an antidote for snake venoms comes from 2016. Due to oral bioavailability it is considered as a potential first-line field-treatment for snakebite envenomation, which could be applied before provision of definitive medical care.

Oral varespladib

Varespladib methyl (also known as A-002, formerly LY333013 and S-3013) is a secretory phospholipase A2 (sPLA2) inhibitor formerly under development by Anthera Pharmaceuticals as a treatment for

(ACS). Varespladib methyl is an orally

bioavailable In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

prodrug A prodrug is a pharmacologically inactive medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be ...

of the molecule varespladib. From 2006 to 2012, varespladib methyl was under active investigation by Anthera Pharmaceuticals as a potential therapy for several

, including

. In March 2012, Anthera halted further investigation of varespladib per a recommendation from an independent Data Safety Monitoring Board. Varespladib and varespladib methyl were characterised as effective molecules in neutralization of snakes venoms and are under experimental evaluation.

Intravenous varespladib

Varespladib sodium (also known as A-001, previously LY315920 and S-5920) is a sodium salt of varespladib designed for

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

delivery. It was under evaluation by Anthera Pharmaceuticals as an anti-inflammatory sPLA2 inhibitor for the prevention of

(ACS), the leading cause of death for patients with

sickle-cell disease Sickle cell disease (SCD), also simply called sickle cell, is a group of inherited haemoglobin-related blood disorders. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the oxygen-carrying ...

. Elevated

serum Serum may refer to: Biology and pharmacology *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity *Serous fluid, any clear bodily fluid Places *Serum, Ind ...

levels of sPLA2 have been observed in sickle-cell patients preceding and during ACS episodes. This profound elevation in sPLA2 levels is not observed in sickle-cell patients at steady-state or during a

vaso-occlusive crisis A vaso-occlusive crisis is a common painful complication of sickle cell anemia in adolescents and adults. It is a form of sickle cell crisis. Sickle cell anemia – most common in those of African, Hispanic, and Mediterranean origin – leads to ...

, or in patients with

respiratory diseases Respiratory diseases, or lung diseases, are pathology, pathological conditions affecting the organs and tissues that make gas exchange difficult in Breathing, air-breathing animals. They include conditions of the respiratory tract including the t ...

such as

pneumonia Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...

. A reduction in serum sPLA2 levels, for example through

blood transfusion Blood transfusion is the process of transferring blood products into a person's Circulatory system, circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used ...

, reduces the risk of an ACS, suggesting that sPLA2 plays an important role in the onset of ACS. Anthera Pharmaceuticals acquired varespladib sodium from Lilly and

Shionogi is a Japanese pharmaceutical company best known for developing Crestor. Medical supply and brand name also uses katakana (シオノギ). Shionogi has business roots that date back to 1878, and was incorporated in 1919. Among the medicines pr ...

in 2006. In 2007, the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) granted varespladib sodium

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

status for its potential to treat patients with sickle-cell disease, which was later withdrawn. In 2009, Anthera Pharmaceuticals completed a Phase II study of varespladib sodium in subjects with sickle cell disease at risk for ACS. Inhibitory effect on snake venoms Snakebite envenomation can cause local tissue damage, with edema, hemorrhage, myonecrosis, and systemic toxic responses, including organ failure. In an early report on inhibition of snake venom toxicities, varespladib, and its orally bioavailable prodrug methyl-varespladib (LY333013) showed strong inhibition of 28 types of svPLA2s from six continents. Varespladib treatment exerted a significant inhibitory effect on snake venom PLA₂ both ''in vitro'' and in ''vivo''. Hemorrhage and myonecrosis initiated by D. acuts, A. halys, N. atra, and B. multicinctus in an animal model were significantly reversed by varespladib. Furthermore, edema in gastrocnemius muscle was also attenuated. The sPLA2 inhibitor, LY315920 (varespladib sodium), and its orally bioavailable prodrug, LY333013 (varespladib methyl) were highly effective in preventing lethality following experimental envenoming by M. fulvius in a porcine animal model. Considering that some of the toxins of snake venoms are enzymes, the search for low molecular weight enzyme inhibitors that could be safely administered immediately after a snakebite re-focused scientists' attention on varespladib. Its ability to neutralize the enzymatic and toxic activities of three isolated PLA2 toxins (from medically important snakes found in different region around the world) of structural groups I (pseudexin) and II (crotoxin B and myotoxin I) was evaluated. The results obtained showed that varespladib was able to neutralize the in vitro cytotoxic and in vivo myotoxic activities of purified PLA2s of both the structural group I (pseudexin) and II (myotoxin-I and crotoxin B), however further detailed analysis are needed. Varespladib also effectively inhibited the non-enzymatic myotoxic activity of the snake venom PLA2-like protein (MjTX-II). Co-crystallization of varespladib with MjTX-II toxin revealed that the compound binds to a hydrophobic channel of the protein. Such interaction blocks fatty acids binding, thus inhibiting allosteric activation of the toxin. This leads to the toxin losing its ability to disrupt cell membranes. In 2019, the U.S.

(FDA) designated varespladib

status for its potential to treat snakebite, without being FDA approved for Orphan Indication.

Mechanism

Prodrug activation

Varespladib methyl, in contrast to varespladib, is orally

and after absorption from the

GI tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

, it undergoes rapid

ester In chemistry, an ester is a compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds contain a distin ...

hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

to the active molecule – varespladib.

sPLA2 inhibition

Increased levels of sPLA2 have been observed in patients with

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

, and may lead to both acute and chronic disease manifestations by promoting vascular inflammation. Plasma levels of sPLA2 can predict coronary events in patients who recently suffered an ACS as well as in those with stable

coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of cardiovascular disease, heart disease involving Ischemia, the reduction of blood flow to the cardiac muscle due to a build-up ...

. Furthermore, sPLA2 remodels

lipoproteins A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a triglyceride and cholesterol center, sur ...

, notably

low-density lipoproteins Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...

(LDL) and their receptors, which are responsible for removing

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

from the body. This remodeling can lead to increased deposition of LDL and cholesterol in the

artery An artery () is a blood vessel in humans and most other animals that takes oxygenated blood away from the heart in the systemic circulation to one or more parts of the body. Exceptions that carry deoxygenated blood are the pulmonary arteries in ...

wall. In combination with chronic vascular inflammation, these deposits lead to

atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...

. Varespladib inhibits the IIA, V and X

of sPLA2 to reduce inflammation, lower and modulate

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

levels, and reduce levels of

C-reactive protein C-reactive protein (CRP) is an annular (ring-shaped) pentameric protein found in blood plasma, whose circulating concentrations rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin ...

(CRP) and

interleukin-6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...

(IL-6), both indicators of inflammation.

Snake venom antidote activity

sPLA2 is also present in snake venoms and implicated in their toxicity. It plays a role in the morbidity and mortality from snakebite envenomations, triggering induced cell lysis, disrupted

hemostasis In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel (the opposite of hemostasis is hemorrhage). It is the first stage of wound healing. Hemostasis involves three ...

, and diminished oxygen transport, as well as myotoxicity and neurotoxicity which can lead to paralysis. Varespladib methyl, as well as varespladib, were found to be inhibitors of the sPLA2 of snake venoms. Varespladib methyl was less potent than varespladib. Both showed activity against a broad spectrum of different snake venoms originating from six continents. They protected rodents against neurotoxicity and hemostatic toxicity, increasing survival of envenomed animals. Varespladib also effectively inhibited in vitro and in vivo the non-enzymatic myotoxic activity of snake venom's PLA2-like protein (MjTX-II). Co-

crystallization Crystallization is a process that leads to solids with highly organized Atom, atoms or Molecule, molecules, i.e. a crystal. The ordered nature of a crystalline solid can be contrasted with amorphous solids in which atoms or molecules lack regu ...

of varespladib with MjTX-II toxin (PDB code: 6PWH) revealed that the drug binds to a hydrophobic channel of the protein. This blocks fatty acids from binding there, thus inhibiting their

allosteric In the fields of biochemistry and pharmacology an allosteric regulator (or allosteric modulator) is a substance that binds to a site on an enzyme or receptor distinct from the active site, resulting in a conformational change that alters the p ...

activation of the toxin, thereby impairing its ability to disrupt cell membranes.

References

External links

Varespladib methyl at Anthera.com

Varespladib sodium at Anthera.com

Varespladib methyl Phase III study at ClinicalTrials.gov

Varespladib sodium Phase II study at ClinicalTrials.gov
{{Tryptamines 1-Alkyltryptamines 2-Alkyltryptamines Carboxamides Carboxylic acids 4-Hydroxytryptamines Beta-Ketotryptamines