Nature as the Blueprint for

a Family of First-in-class

Therapeutics

Unlocking the Full Potential of Omega 3 Biology

The health benefits of an omega-3 fatty acid rich diet were first recognized when populations with traditionally high intake of fish and seafood were found to be less susceptible to cardiovascular-related mortality caused particularly by arrhythmia and sudden cardiac death. It turns out this and a variety of other beneficial health effects are actually mediated by omega-3 fatty acid-derived metabolites, called “epoxyeicosanoids”.

Epoxyeicosanoids as a novel class of omega-3 fatty acid-derived bioactive molecules are generated via the cytochrome P450 (CYP) epoxygenase pathway. Enzymes in the CYP pathway help to transform the major dietary fish oil omega-3 fatty acids, EPA and DHA, to omega-3 epoxyeicosanoids such as 17,18-EEQ and 19,20-EDP. Preclinical studies performed by OMEICOS and its partners showed that these molecules display cardioprotective, neuroprotective, anti-inflammatory and immune-modulating properties making them a potentially attractive novel class of bioactive molecules for the prevention and treatment of several diseases.  
However, these molecules have proven to be highly unstable and are rapidly converted into metabolites with either no or less favourable biological activities. Furthermore, the formation and activity of these beneficial molecules vary from individual to individual due to a person’s unique genetic make-up and several diseases negatively impact this process, as well. Taken together, the bioavailability of epoxyeicosanoids in the human body is largely unpredictable.
Our approach aims to overcome these limitations in addition to making the drugs orally available. Based on in-depth structure-activity-relationship studies, we have generated a library of first-in-class, metabolically stable, synthetic analogs of epoxyeicosanoids that mimic their biological activity and are independent of dietary supplements and genetic factors that can modulate cellular metabolite levels. Our small molecule compounds are orally available and show significantly improved biological activity and pharmacokinetic properties compared to their natural counterpart.

A Safer, Patient-friendly Therapy for Atrial Fibrillation

Normally, the heart contracts and relaxes in a regular fashion – on average with 70 beats per minute and 100.000 beats per day. Atrial fibrillation, or AFib for short, is the most common cardiac arrhythmia characterized by an irregular and often rapid heartbeat. This can lead to severe instability of blood circulation causing blood clots, stroke, heart failure and other cardiac complications.

Atrial Fibrillation: A Major Public
Health Concern

Limited therapeutic options as well as increasing numbers of patients suffering from AFib result in a very high unmet medical need for a safe and efficient new anti-arrhythmic drug.

In preclinical trials, our compounds could not only stabilize the heart rhythm, but also provide curative effects to the diseased heart by preventing the remodeling of its electrical and structural properties.

1 Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analyis, Odutayo A. et al., 2016

2 Lifetime Risk for Development of Atrial Fibrillation, The Framingham Heart Study, Lloyd-Jones DM et al., 2004

3 Estimates of Current and Future Incidence and Prevalence of AtrialFibrillation in the U.S. Adult Population, Colilla S. et al., 2013

4 Chugh, S. S. et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 129, 837–847 (2013)

5 Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060,  Krijthe Bouwe P. et al., 2013

In contrast to all other drugs currently on the market that act almost exclusively via direct inhibition of ion channels, our molecules activate an endogenous cardio-protective signaling pathway through highly selective binding to a so far undisclosed G-protein coupled receptor complex.

A Multimodal Approach to Treat AFib

The first goal in AFib is to stabilize the heart rhythm while leaving other key heart beat parameters unchanged.

AFib represents constant stress on the heart muscle cells, the cardiomyocytes, and supporting tissues in that organ. Improved mitochondrial function should lead to fewer cells dying due to this stress.

The heart is a complex organ and for it to function properly, the core muscle cells and other cell types and tissues have to work closely together. In AFib patients, scarring and fibrosis occurs throughout the organ severely disturbing that system.

 

A Non-invasive Therapeutic Option to Treat Vision Loss

In macular edema fluid build-up causes this small area at the center of the eye’s retina, crucial for sharp vision, to swell and thicken, thereby distorting vision. Macular edema also occurs due to abnormal formation of very small and leaky blood vessels in the retina, also known as choroidal neovascularization (CNV).

Macular edema and CNV contribute to loss of vision in several ocular diseases with a chronic inflammatory mechanism, including wet age-related macular degeneration, or AMD for short, and diabetic retinopathy. AMD is the leading cause of severe vision loss in individuals over 65 years of age.

In 2017, OMEICOS established an US-based subsidiary, OMEICOS Ophthalmics, located in Boston, MA, which focuses entirely on the further validation of our therapeutic concept in ophthalmological indications and subsequently on the clinical development program of individual compounds, which will be orally available and may reduce the burden of repeated injections into the eye, as current therapies are administered.

Our Scientific Library

Chemistry
Scientific Evidence
Therapeutic potential of 17, 18-EEQ analogs
Chemistry

Development of metabolically robust 17,18-EEQ analogs, Falck et al. J Med Chem 2011

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Scientific Evidence

Relevance of soluble Epoxide Hydrolase (enzyme which is quickly de-activating 17,18-EEQ) in heart failure development – supporting evidence for relevance of CYP pathway as a therapeutic target in heart diseases; Monti et al. Nature Med 2008
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CYP enzymes efficiently convert EPA and DHA to novel bioactive lipid mediators that probably contribute to the cardiovascular beneficial effects of dietary omega-3 fatty acids. CYP2J2, the major CYP epoxygenase in the human heart prefers EPA as substrate and converts it to 17,18-EEQ.
C Arnold et al., JBC 2010
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Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids
Konkel and Schunck, Biochim Biophys Acta. 2011
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CYP-eicosanoids - a new link between omega-3 fatty acids and cardiac disease?
Westphal et al., Prostaglandins Other Lipid Mediat. 2011
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In transgenic mice overexpression of human epoxygenase CYP2J2 confers protection against ventricular tachycardia and atrial fibrillation.
Westphal et al., PLOS One 2013
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17,18-EEQ becomes the major upregulated EPA-metabolite when omega-3 fatty acid supplementation is given to man.
Fischer et al., J Lipid Res 2014
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Therapeutic potential of 17, 18-EEQ analogs

Therapeutic potential of omega-3 fatty acid-derived epoxyeicosanoids in cardiovascular and inflammatory diseases, Schunck et al. Pharmacol Ther 2018

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17,18-EEQ as active EPA metabolite, mediating reduction of chorideal neovascularization, Yanai et al. PNAS 2013

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17,18-EEQ and stable synthetic analog C21 reduce chorideal neovascularization via a immunomodulatory mechanism of action, Hasegawa et al. PNAS 2017

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