INTRODUCTION

Polyunsaturated Fatty Acids (PUFAs) have long been known to affect the central nervous system (CNS). However, only recently has the research community discovered more about their functions with respect to the brain. While arachidonic acid is a dominant fatty acid in brain tissue, docosahexaenoic acid (DHA) is the major PUFA present. DHA is derived from eicosapentaenoic acid (EPA).  Miraxion is Amarin's ultra pure EPA. 

Amarin is therefore employing a novel, proprietary technology platform based on knowledge of the chemical nature and highly vascular environment of the brain to develop pharmaceuticals in the area of neurology. The Company’s unique technology of lipophilic drugs is predominantly fat-soluble, making for easy transportation across the blood-brain barrier. This is important since the majority of drugs currently available to treat neurological and psychiatric disorders have mechanisms of action targeting receptors of the brain (surface proteins embedded in the phospholipid membranes) or neurotransmitters in the brain. Amarin’s technology targets the bio-chemical imbalances of the phospholipids themselves. This can be compared to the following: just as oil and water do not mix, the majority of drugs which easily dissolve in water do not readily penetrate the brain.

Epidemiological and clinical data suggest that an altered membrane composition, one characterized by a depletion of several metabolites of EPA, is related to many neurological and psychiatric disorders. Data from in vivo and post-mortem studies have provided evidence that membrane abnormalities are involved in schizophrenia and mood disorders. Within this area, Amarin’s first lipophilic product, Miraxion™, is in development for Huntington’s disease, depressive disorders and Parkinson’s disease.

BACKGROUND

All cells have a cell surface membrane (also known as a plasma membrane) that is very fragile, and its role is to hold the cell together, helping to control what substances go in and out. It is partially permeable, allowing only some substances to pass through it. The membrane has a complex structure consisting of a phospholipid bilayer and different types of proteins (see Figure below).  

PHOSPHOLIPIDS

Phospholipids are responsible for maintaining a membrane’s structure, modulating protein structure and function, cellular signaling, and gene regulation.

Within the brain, phospholipids are particularly important in dendrites and synapses and are a major determinant of the quaternary structure of all membraneassociated proteins.

Additionally, almost all neuronal proteins are incorporated into or attached to phospholipid membranes, and all neuronal receptors are linked to phospholipid signal transduction mechanisms — this is the case for dopamine, serotonin, glutamate, GABA, acetyl-choline, histamine, growth factor, and cytokine receptors. Phospholipids are further required for post-receptor signal transduction processes of all neurotransmitters.

Membranes are enormously complex, with thousands of functional components that can be arranged in millions of different ways.  Far from being mere support scaffolding, phospholipids and their derivatives are thus central to cellular function.  Amarin's Miraxion (EPA) acts on these important phopholipids, in particular on the Sn2 position.  See figure below. 

The human brain is made up of approximately 60% fat (phospholipid) by weight and approximately 30% protein, and is very soft and fluid—made that way by fatty acids.

FAMILIES OF PUFAs

Two families of PUFAs are the n-6 (or omega-6) family, derived from linoleic acid, and the n-3 (or omega-3) family, derived from the alpha-linolenic acid. These two fatty acids are essential since they can not be made within the body, and thus must come from the diet. Additionally, fatty acids are not able to be interconverted.

Dihomogammalinolenic (DGLA), arachidonic (AA), eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids are the precursors for so-called eicosanoids, prostaglandins, and other oxygenated derivatives. There are dozens of derivatives, each of which has a specific spectrum of actions. The derivatives are produced locally when they are needed and are almost instantly locally destroyed. The enzymes involved in the metabolism of these fatty acids to eicosanoids are the cyclo-oxygenases (COX-1 or COX-2) and related systems, which give rise to prostaglandins and thromboxanes; lipoxygenases give rise to leukotrienes.

AA-derived prostaglandins in neuronal membranes are proinflammatory and can even trigger apoptosis. AA is therefore an important membrane fatty acid which, if ‘in control’, is essential for normal cell metabolism, but if it gets ‘out of control’, initiates a pro-inflammatory cascade. In the brain, AA is one of the most important fatty acids involved in cell signaling. It is now believed that an over-active Phospholipase A2 (PLA2) via an abnormal stimuli, releases AA from neuronal membranes.  It is believed that Amarin's Miraxion can counterbalance this over-active PLA2 and regulate the pro-inflammatory AA cascade. 

The animation below depicts the role of Miraxion and its metabolites on the neuron phopholipids, AA pathway and ultimately highlights its neuroprotective properties. (Press the Play button to commence animation). The animation is approx 6 mintues long.

 [ For a longer version of the animation (approx 10 mins) please click here ]

Amarin’s technology is based on the fact that EPA by itself, or via its metabolites, is an important compound with pharmacological properties. EPA and AA are termed by experts as functional fatty acids, which have polytropic effects; DHA is termed as one with structural functions. 

METABOLISM OF EPA

EPA is a normal intermediate in human metabolism and is found in small quantities in all normal tissues. It is moved intact from lipid fraction to lipid fraction by various enzymes going under the general name of acyltransferases. It may be found as a free fatty acid, or esterified to cholesterol or glycerol or a phospholipid. It may be found in any phospholipid class, usually attached to the Sn2 carbon (see above) and found in greatest abundance in phosphatidyl-ethanolamine.

EPA is metabolised in four main ways:

(1) As with any other fatty acid, it can be converted into carbon dioxide and water by beta oxidation.

(2) It may be converted along the n-3 pathway to docosapentaenoic acid (22:5n-3) and then to docosahexaenoic acid (22:6n-3, DHA).

(3) Very small amounts may be converted to eicosanoids by cyclo-oxygenase (COX)-1, COX-2, or by a range of lipoxygenases, including 5, 12, and 15-lipoxygenases.

(4) Phospholipase C (PLC) may split the phosphorus and head group from the phospholipids, leaving a diacylglycerol (DAG), which often contains EPA or AA at the Sn2 position. PLCs, such as PLA2, may have high activity toward phospholipids rich in AA or EPA, with much lower activity towards other fatty acids.