Identification of mechanism-based therapies to treat arrhythmogenic cardiomyopathy by resolving perturbations in regulatory lipid signaling

Abstract The goal of this SBIR Phase I proposal is to demonstrate safety and provide a solid rationale for targeting eicosanoid-driven inflammation through inhibition of the soluble epoxide hydrolase (sEH) enzyme in patients with arrhythmogenic cardiomyopathy (ACM). ACM is a heritable heart-muscle disease caused by a genetic defect in cardiac desmosomes, resulting in the progressive loss of ventricular muscle and its replacement by fibrofatty tissue. ACM affects 1 in 5000 persons and is clinically characterized by life-threatening ventricular arrhythmias and progression to debilitating heart failure. It is a common cause of sudden death in young people, especially athletes. Current therapies are mostly palliative, focused on preventing sudden death with implantable cardioverter defibrillators. There is an unmet need for mechanism-based therapies that can modify disease progression and improve quality of life of ACM patients. Substantial evidence shows inflammation is a key feature of ACM disease progression, suggesting ACM represents a chronic inflammatory condition and opening the possibility to alter its natural history with targeted anti-inflammatory therapies. Recent data demonstrate that bioactive lipid mediators formed from the metabolism of polyunsaturated fatty acids (PUFA) can resolve inflammation through a balance of anti- and pro-inflammatory lipid mediators, known as eicosanoids. PUFA-derived epoxy fatty acids (EpFA) are formed by CYP450s and have potent inflammation-resolving properties. However, their beneficial effects are limited by their rapid metabolism into inactive or even pro-inflammatory diols by the sEH enzyme. Notably, these pro-inflammatory diols are significantly increased in patients with ACM, suggesting a potential therapeutic role of inhibiting sEH to restore the balance between EpFA and their diols. EicOsis has developed a small-molecule oral inhibitor of the sEH enzyme, EC5026, and is currently conducting Phase 1 clinical trials in humans. Here, we propose to determine the cardiac safety profile of EC5026 and provide additional scientific rationale for targeting eicosanoid-driven inflammation in patients with ACM through sEH inhibition. We will attain these goals by: 1) determining the cardiac safety profile of oral EC5026 analyzing previously collected continuous electrocardiogram data from an ongoing Phase 1b multiple ascending dose study in healthy volunteers; 2) characterizing the baseline alterations of eicosanoids and other inflammatory mediators in ACM patients and compare it to non-affected family matched controls; and, 3) evaluating the effects of EC5026 in human induced pluripotent stem cells (hiPSC) cardiac myocytes derived from patients with ACM. We expect to demonstrate that inhibiting the sEH enzyme with oral EC5026 is a safe therapeutic approach with the potential of successfully modifying the underlying inflammatory component of ACM, providing a strong rationale to seek a Phase II SBIR application to conduct a pilot clinical trial of EC5026 in patients with ACM.