Varespladib methyl
Encyclopedia
Varespladib methyl is a secretory phospholipase A2 (sPLA2) inhibitor under development by Anthera Pharmaceuticals
as a treatment for acute coronary syndrome
(ACS). Varespladib methyl is an orally bioavailable prodrug
of the molecule varespladib
. It is currently under active investigation in a Phase III clinical trial called VISTA-16.
, 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.
Furthermore, sPLA2 remodels lipoproteins, notably low-density lipoproteins (LDL) and their receptors, which are responsible for removing cholesterol
from the body. This remodeling can lead to increased deposition of LDL and cholesterol in the artery
wall. In combination with chronic vascular inflammation, these deposits lead to atherosclerosis
.
Varespladib inhibits the IIA, V and X isoforms of sPLA2 to reduce inflammation, lower and modulate lipid
levels, and reduce levels of C-reactive protein
(CRP) and interleukin-6 (IL-6), both indicators of inflammation.
and Shionogi & Co., Ltd.
, and was acquired by Anthera Pharmaceuticals in 2005.
A Phase II study by Anthera successfully 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 CRP and other inflammatory biomarkers. Varespladib methyl has also been shown to further reduce LDL and inflammatory biomarker levels when administered in conjunction with a cholesterol lowering statin
therapy.
In 2010, a Phase III study entitled VISTA-16 was launched to evaluate the safety and efficacy of short-term treatment with varespladib methyl in subjects with ACS.
Anthera Pharmaceuticals
Anthera Pharmaceuticals, Inc. is a pharmaceutical company that specializes in developing treatments for serious cardiovascular and autoimmune diseases...
as a treatment for acute coronary syndrome
Acute coronary syndrome
Acute coronary syndrome is usually one of three diseases involving the coronary arteries: ST elevation myocardial infarction , non ST elevation myocardial infarction , or unstable angina ....
(ACS). Varespladib methyl is an orally bioavailable prodrug
Prodrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
of the molecule varespladib
Varespladib
Varespladib is an inhibitor of the IIa, V, and X isoforms of secretory phospholipase A2 . The molecule acts as an anti-inflammatory agent by disrupting the first step of the arachidonic acid pathway of inflammation...
. It is currently under active investigation in a Phase III clinical trial called VISTA-16.
Mechanism
Increased levels of sPLA2 have been observed in patients with cardiovascular diseaseCardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, and may lead to both acute
Acute (medicine)
In medicine, an acute disease is a disease with either or both of:# a rapid onset, as in acute infection# a short course ....
and chronic
Chronic (medicine)
A chronic disease is a disease or other human health condition that is persistent or long-lasting in nature. The term chronic is usually applied when the course of the disease lasts for more than three months. Common chronic diseases include asthma, cancer, diabetes and HIV/AIDS.In medicine, the...
disease manifestations by promoting vascular inflammation. Plasma
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
levels of sPLA2 can predict coronary events in patients who recently suffered an ACS as well as in those with stable coronary artery disease.
Furthermore, sPLA2 remodels lipoproteins, notably low-density lipoproteins (LDL) and their receptors, which are responsible for removing cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
from the body. This remodeling can lead to increased deposition of LDL and cholesterol in the artery
Artery
Arteries are blood vessels that carry blood away from the heart. This blood is normally oxygenated, exceptions made for the pulmonary and umbilical arteries....
wall. In combination with chronic vascular inflammation, these deposits lead to atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
.
Varespladib inhibits the IIA, V and X isoforms of sPLA2 to reduce inflammation, lower and modulate lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
levels, and reduce levels of C-reactive protein
C-reactive protein
C-reactive protein is a protein found in the blood, the levels of which rise in response to inflammation...
(CRP) and interleukin-6 (IL-6), both indicators of inflammation.
Clinical Development
Varespladib methyl was originally developed jointly by Eli Lilly and CompanyEli Lilly and Company
Eli Lilly and Company is a global pharmaceutical company. Eli Lilly's global headquarters is located in Indianapolis, Indiana, in the United States...
and Shionogi & Co., Ltd.
Shionogi
is a Japanese pharmaceutical company best known for developing Crestor. Medical supply and brand name also uses Shionogi .Shionogi has business roots that date back to 1878, and was incorporated in 1919. Among the medicines produced are for hyperlipidaemia, antibiotics, and cancer medicines.In...
, and was acquired by Anthera Pharmaceuticals in 2005.
A Phase II study by Anthera successfully 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 CRP and other inflammatory biomarkers. Varespladib methyl has also been shown to further reduce LDL and inflammatory biomarker levels when administered in conjunction with a cholesterol lowering statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...
therapy.
In 2010, a Phase III study entitled VISTA-16 was launched to evaluate the safety and efficacy of short-term treatment with varespladib methyl in subjects with ACS.