Ethyl-EPA, also known as Miraxion or LAX-101, is a novel compound that may function as a neuroprotectant by preventing the degradation of brain tissue through a variety of proposed mechanisms. The compound might inhibit harmful enzymes known as phospholipases and might also stabilize the phospholipid components of cell membranes and mitochondria, both of which play important roles in cell regulation and brain function. Ethyl-EPA might also have anti-inflammatory effects. Clinical trials, however, show mixed results; the TREND-HD study indicated that ethyl-EPA has no benefit over short time periods (6 months), but might help motor symptoms of HD over long periods of time. Further study is necessary to determine whether or not ethyl-EPA can be used to treat HD.
Table of Contents
What is a phospholipase?^
A phospholipase is a type of enzyme that converts the phospholipids on cell membranes into free fatty acids and other fat-soluble substances. Phospholipases are grouped into four major classes: A, B, C, and D. It turns out that in the case of several neurodegenerative diseases, including Alzheimer’s and possibly HD, increased activity of phospholipase A2 (PLA2) may be responsible for an abnormally large release of free fatty acids from membrane phospholipids, as well as the accumulation of lipid peroxides. Lipid peroxidation is defined as the process whereby free radicals “steal” electron from the lipids of cell membranes, resulting in cell damage and increased production of even more free radicals. (For more information on lipid peroxidation, click here). Thus, an initial increase in PLA2 activity, along with the accumulation of lipid peroxide products, may set in motion a type of “snowball” effect whereby harmful products such as lipid peroxides and free radicals are produced, molecules that then go on to generate even more harmful substances.
What is Ethyl-EPA’s primary mechanism of action?^
Ethyl-EPA is thought to act as a PLA2 inhibitor. As discussed earlier, increased PLA2 activity may degrade nerve cell membranes by initiating the release of free fatty acids from the membranes. Fatty acids are an essential component of nerve cell membranes; membrane fluidity, which is necessary for normal cell functioning and health, depends almost entirely on the precise balanced composition of fatty acids and phospholipids in the membrane. (For more information on the importance of membrane fluidity, click here). The effect of taking fatty acids away from the membrane and altering its composition may affect the membrane fluidity in such a way that important nutrients may become less able to enter the cell and harmful substances may become more able to enter. Oxygen, glucose, and other nutrients that the cell needs to survive all must pass through the membrane before entering the cell. Conversely, the membrane must block harmful substances so they don’t enter the cell. Thus, by initiating the release of free fatty acids from membranes, increased PLA2 activity indirectly puts nerve cells in danger by decreasing the overall effectiveness of the nerve cell membrane. It follows that if ethyl-EPA is able to inhibit (prevent the activity of) PLA2, the release of free fatty acids would be prevented and the normal functioning of the membrane would be maintained.
How does Ethyl-EPA reduce inflammation?^
Increased PLA2 activity also contributes to inflammation, which is a process that plays a large role in the course of HD. Here’s how the inflammation process works: in response to any form of trauma or infection, certain cells in the body produce messenger substances called cytokines. (For more information on inflammation, click here). These cytokines, in turn, act upon another group of cells, causing them to synthesize and release PLA2. The effect is like opening the flood-gates. When PLA2 is released, it breaks down the cell membrane (as mentioned previously) and causes the release of a sea of inflammatory agents such as prostaglandins and leukotrienes. This increase in inflammatory agents sets the stage for the production of free radicals and reactive oxygen species, and hence for lipid peroxidation and further damage to membrane proteins. By inhibiting PLA2, ethyl-EPA controls the inflammation process and prevents it from spiraling out of control.
Research on Ethyl-EPA^
Puri, et al. (2002) conducted a six-month controlled study of seven patients with advanced Huntington’s disease (four received placebo, three received ethyl-EPA). The study was conducted at Hammersmith Hospital in London. Six months following the initiation of treatment, all of the patients who received ethyl-EPA showed significant improvement in comparison to the placebo group as measured by the orofacial component of the Unified Huntington’s Disease Rating Scale (UHDRS). All patients receiving placebo experienced worsening of the disease, as measured by the orofacial component of the UHDRS. Overall, there was an average 34% improvement for the patients receiving ethyl-EPA and an average 23% decline for the patients receiving placebo. Furthermore, there were no adverse effects associated with the treatment.
In addition to the orofacial component, patients treated with ethyl-EPA showed significant improvement on the total movement score of the UHDRS in comparison to the patients receiving placebo (an average 16% improvement for the ethyl-EPA group versus an average 38% decline for the placebo group). Furthermore, brain MRI scans of two patients on ethyl-EPA demonstrated an increase in overall brain size. Conversely, MRI scans of two patients on placebo each showed a decrease in brain size, consistent with neurodegenerative progression in patients with Huntington’s disease.
Vaddadi, et al. (2002) performed a controlled clinical study at Monash University in Melbourne, Australia at the same time as the study done by Dr. Puri’s group above. In the Vaddadi group’s study, seventeen people with Huntington’s disease were treated for nineteen to twenty months with a ethyl-EPA prototype drug. When the results from the Puri study became available, Vaddadi’s study was halted on ethical grounds in order to offer treatment with ethyl-EPA to those who were on placebo. Before it was halted, however, valuable data in support of the efficacy of ethyl-EPA was obtained. On the UHDRS motor sub-scale, seven of eight patients on placebo deteriorated during the trial, whereas five of nine patients receiving active drug improved. The other primary measurement used was the Rockland-Simpson Dyskinesia Rating Scale. In the placebo group, six of eight patients deteriorated, and in the active drug group, seven of nine improved. As in the Puri study, no adverse effects associated with treatment were observed. Even though these two clinical trials each included only a small group of patients, the positive results were striking. The drug seemed like it had the potential to have a significant clinical benefit in the treatment of HD.
Laxdale Limited (2001) decided to further test the efficacy of the drug by conducting a 135-patient phase III controlled study. Laxdale Limited began a large-scale study in 2001. The study tested 135 subjects at six different centers in the United States, Canada, the United Kingdom, and Australia. This study was a phase III double-blind, placebo-controlled study in which the drug was tested over the course of 12 months. Subjects were rated after 12 months of using ethyl-EPA using the Total Motor Score 4 (TMS 4) subscale of the United Huntington’s Disease Rating Scale (UHDRS), the standard rating scale for trials in this disease. The results of this study were announced In February 2003, when it was revealed that statistical significance was not achieved in the entire study patient population. However, this lack of significance was explained primarily by the fact that many patients did not fully follow the study procedure. In those patients who did comply with the protocol, a trend to statistical significance was observed. Only 1 out of the 135 participants experienced a treatment related side effect (gastrointestinal upset).
When the clinical data was analyzed further, it was found that the group of patients with a CAG repeat length of less than 45 showed a statistically significant improvement over those patients receiving placebo, whereas patients with a CAG repeat length of greater than 45 did not. It is believed that there is a direct link between CAG repeat length and age of onset, disease progression and clinical symptoms. It is estimated that 65% of people with HD have a CAG repeat length of less than 45. This means that ethyl-EPA has the potential to improve motor function in over 65% of people with HD.
This finding, however, does not rule out the possibility that ethyl-EPA can help people with higher CAG counts. There is a realistic possibility that there is a confound at play here: on average, people with more than 45 repeats have an earlier onset of HD. Because the drug may have greater benefits for people with later disease onset, these patients with more than 45 repeats may not have responded as well to the treatment. Of course, without further study, there is no way to conclude whether the number of CAG repeats does or does not affect the effectiveness of the drug.
Although the previous study did not conclusively prove the effectiveness of ethyl-EPA in treating HD, the results were promising and valuable information was obtained. This information, along with discussions with the FDA and feedback from the European Medicines Evaluation Agency (“EMEA”), will be used to design another ethyl-EPA study. CAG repeat lengths in the patients will be an important component in the design of the next study. It will allow experimenters to more accurately target patients with this specific gene variant, particularly relating to age and onset of the disease. The Huntington’s Study Group will be conducting the study in people who have mild to moderate Huntington’s disease. Researchers at 43 sites in the United States and Canada will each enroll approximately 7-8 research subjects. Results are expected sometime in late 2006.
Most Recent Research^
TREND-HD (2008): Ethyl-EPA showed mixed results in a phase III clinical trial, called TREND-HD. This study, conducted by the Huntington Study Group, had two phases. In the first phase, 316 HD adults were randomly assigned to either the treatment group, which received 1 gram of ethyl-EPA twice per day, or the control group, which received a placebo. This was a double-blind study; neither doctor nor patient knew what the patient was receiving, so as to remove any potential bias from the experiment. After six months, the two groups were compared, and the results were grim; there was no significant difference between the two groups on the TMS 4; patients in the treatment group did not have improved motor or cognitive symptoms relative to the placebo group.
However, the study continued, as the investigators wanted to know whether a longer-term treatment with ethyl-EPA might be useful. The second phase of the study lasted another six months. For this phase, the 192 patients who remained involved in the study were all treated with ethyl-EPA. Patients were not told whether they were given placebo or ethyl-EPA during the first 6 month time period. At the end of the study, the patients that had been taking ethyl-EPA for a full year had better scores on the TMS 4 than patients who had received placebo for 6 months then ethyl-EPA for 6 months. They had better scores on tests of chorea and motor symptoms, but there was no difference in the two groups on measures of cognition, mood, or function. These results suggest that ethyl-EPA might be a useful treatment, particularly with those with fewer than 45 CAG repeats, but that its effects are only seen after a longer period of time. The scientists concluded that ethyl-EPA is not effective for short treatment times, but should be studied over longer time periods
For Further Reading^
- Farooqui, A.A. et al. (1997). “Phospholipase A2 and its role in brain tissue.” J. Neurochem 69(3): 889-901.
This is a technical review article that explains the various mechanisms through which phospholipase A2 exerts its effects in the brain.
- Puri, B.K. et al. (2001). “Impaired phospholipid-related signal transduction in advanced Huntington’s disease.” Exp Physiol. 86(5): 683-5.
This is a scientific article that discusses the role that phospholipids play in signal transduction and how this process becomes impaired in HD.
- Puri, B.K. et al. (2002). “MRI and neuropsychological improvement in Huntington disease following ethyl-EPA treatment.” Neuroreport 13(1): 123-6.
This article of medium difficulty outlines the protocol of the study done by Dr. Puri in which three patients were treated with ethyl-EPA and four with placebo. It is of medium difficulty.
- Vaddadi, K.S. et al (2002). “A randomised, placebo-controlled, double blind study of treatment of Huntington’s disease with unsaturated fatty acids.” Neuroreport 13(1): 29-33.
This article outlines the protocol of the study done by Dr. Vaddadi in which eight patients received placebo and nine received an ethyl-EPA prototype drug. It is of medium difficulty.
- Huntington Study Group TREND-HD Investigators. Randomized controlled trial of ethyl-eicosapentaenoic acid in Huntington disease: the TREND-HD study. Arch Neurol. 2008 Dec;65(12):1582-9. Erratum in: Arch Neurol. 2009 Mar;66(3):305 This is the most recent study done on ethyl-EPA, and is of medium difficulty
D. McGee, 1-23-06, updated by M. Hedlin, 6-30-11