Investigating the broader efficacy of sEH inhibition and specifically our IND candidate, EC5026, has indicated that it is efficacious against chemotherapy induced peripheral neuropathy (CIPN). This painful neuropathy develops from chemotherapy treatment, is notoriously difficult to treat, and can lead to discontinuation of life-prolonging cancer treatments. Thus, new therapeutic approaches are urgently needed. We propose here to test the efficacy of our soluble epoxide hydrolase inhibitor, EC5026, and a potential backup, EC5029, for their efficacy in CIPN and to characterize this activity with three classes of chemotherapeutics in models of CIPN. We will also investigate if EC5026 has potential drug-drug interaction with approved chemotherapeutics or alters immune cells function. We will assess the effects of sEHI on the lipid metabolome and probe for changes in endoplasmic reticulum stress and axonal outgrowth in neurons. The PK/ADME properties of EC5026 have been determined and a pilot 28-day safety study in dogs has been completed with good results. We propose here to more fully characterize the analgesic potential of our compound and investigate on and off target actions in CIPN models and model systems relevant to cancer therapy.
Public Health Relevance Statement: Project Narrative Initial data investigating the broader efficacy of the EicOsis IND candidate EC5026 indicate efficacy against the pain of chemotherapy induced peripheral neuropathy (CIPN). The overall goal of EicOsis is to develop a drug candidate for IND enabling studies for the treatment of diabetic neuropathic pain. However, because CIPN is a condition with no adequate treatment, we propose to further explore efficacy and characterize the activity of EC5026 and a backup EC5029 in this chronic pain model.
Project Terms: Absence of pain sensation; Analgesics; Anti Inflammatory Analgesics; Arachidonic Acids; Attenuated; Axon; Back; base; Biochemical; Biological; Biological Assay; Biological Models; Cancer Patient; cancer therapy; Canis familiaris; Cell Culture Techniques; Cell Line; Cell physiology; Cell Survival; Centers for Disease Control and Prevention (U.S.); chemotherapy; Chemotherapy-induced peripheral neuropathy; chronic pain; Clinical; Cyclooxygenase Inhibitors; Cytochrome P450; Data; Development; Development Plans; diabetic; Diabetic Neuropathies; Docosahexaenoic Acids; drug candidate; Drug Interactions; Early treatment; Economic Burden; efficacy testing; endoplasmic reticulum stress; Enzymes; Epoxide hydrolase; Equilibrium; Etiology; experience; Fatty Acids; Funding; Future; Goals; Human Resources; Immune; inhibitor/antagonist; Intractable Pain; Lead; Life; Lipids; Mass Spectrum Analysis; metabolome; Modeling; Neurons; Neuropathy; novel therapeutic intervention; opioid epidemic; Pain; pain model; painful neuropathy; Parents; patient population; Pharmaceutical Preparations; Phase I Clinical Trials; Plasma; Platinum; Polyunsaturated Fatty Acids; pre-clinical; programs; Property; Research; safety study; side effect; Small Business Innovation Research Grant; small molecule; social; Sprague-Dawley Rats; standard of care; Symptoms; taxane; Testing; Tissues; United States; United States National Institutes of Health; Vinca Alkaloids; Work
