SBIR-STTR Award

Direct to Phase II

Diabetic neuropathy (DPN) is a major unmet health concern where over half of the estimated 33 million people in the US with type 1 or type 2 diabetes will develop neuropathy1. There is no FDA-approved disease modifying treatment for preventing or slowing progression of diabetic neuropathy other than a recommendation to maintain glycemic control2 and current treatments are restricted to management of the symptomatic consequences of neuropathy such as pain. It is becoming increasingly appreciated that diabetes also injures both the spinal cord (myelopathy) and brain (encephalopathy) such that diabetes is recognized as a prominent risk factor for developing cognitive dysfunction and Alzheimer’s disease14. Accordingly, agents that prevent or reverse peripheral nerve and/or CNS insults during diabetes are of interest either as standalone agents or for adjunctive use with symptomatic treatments. Epigen has developed expertise around the discovery and development of novel lysophosphatidic acid receptor type 1 (LPAR1) antagonists for the treatment of fibrotic disease. In parallel to the study of diabetic nephropathy data was obtained to suggest that lead compounds discovered at Epigen also benefit endpoints of diabetic neuropathy for both nerve injury and markers for cognitive decline in models. This proposal builds on these data to determine if one such lead compound, EPGN2154, may be developed to treat diabetic neuropathy. The goal of this direct to phase 2 application is to conduct detailed pre-clinical efficacy of EPGN2154 in rat DPN models, along with screening safety to allow nomination of a development candidate. Compounds will be prepared and characterized at Epigen prior to testing at University of California San Diego (UCSD) under the guidance of Dr. Nigel Calcutt. Dr. Calcutt’s laboratory will establish and maintain colonies of diabetic rodents, treat them with test agents provided by Epigen and measure physiological, behavioral and structural indices of peripheral and central neuropathy at assorted times throughout the study. Upon study completion tissue will be dissected and processed for histological and biochemical evaluation to support behavioral measurements. Epigen will conduct additional lead profiling to support candidacy of EPGN2154. Drug distribution will also be evaluated to support mechanistic studies. Compound profiling will include a safety assessment of EPGN2154. These studies will support the advancement of EPGN2154 to IND enabling studies as a prelude to entry into clinical trials for DPN. Public Health Relevance Statement NARRATIVE The overall objective of this project is to identify a new treatment option for diabetic neuropathy a condition that leads to widespread and significant health complications.

Project Terms:
Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Analgesics ; Analgesic Agents ; Analgesic Drugs ; Analgesic Preparation ; Anodynes ; Antinociceptive Agents ; Antinociceptive Drugs ; pain killer ; pain medication ; pain reliever ; painkiller ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Brain ; Brain Nervous System ; Encephalon ; California ; Clinical Trials ; Cytochrome P450 ; Cytochrome P-450 ; Cytochrome P-450 Enzyme System ; Cytochrome P450 Family Gene ; P450 ; Diabetes Mellitus ; diabetes ; Insulin-Dependent Diabetes Mellitus ; Brittle Diabetes Mellitus ; IDDM ; Juvenile-Onset Diabetes Mellitus ; Ketosis-Prone Diabetes Mellitus ; Sudden-Onset Diabetes Mellitus ; T1 DM ; T1 diabetes ; T1D ; T1DM ; Type 1 Diabetes Mellitus ; Type 1 diabetes ; Type I Diabetes Mellitus ; insulin dependent diabetes ; juvenile diabetes ; juvenile diabetes mellitus ; ketosis prone diabetes ; type I diabetes ; type one diabetes ; Non-Insulin-Dependent Diabetes Mellitus ; Adult-Onset Diabetes Mellitus ; Ketosis-Resistant Diabetes Mellitus ; Maturity-Onset Diabetes Mellitus ; NIDDM ; Non-Insulin Dependent Diabetes ; Noninsulin Dependent Diabetes ; Noninsulin Dependent Diabetes Mellitus ; Slow-Onset Diabetes Mellitus ; Stable Diabetes Mellitus ; T2 DM ; T2D ; T2DM ; Type 2 Diabetes Mellitus ; Type 2 diabetes ; Type II Diabetes Mellitus ; Type II diabetes ; adult onset diabetes ; ketosis resistant diabetes ; maturity onset diabetes ; type 2 DM ; type II DM ; type two diabetes ; Diabetic Nephropathy ; Diabetic Kidney Disease ; Diabetic Neuropathies ; diabetes-associated neuropathy ; Disease ; Disorder ; Goals ; Grant ; Health ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; indexing ; Laboratories ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Metabolism ; Intermediary Metabolism ; Metabolic Processes ; Pain ; Painful ; Peripheral Nervous System Diseases ; PNS Diseases ; Peripheral Nerve Diseases ; Peripheral Nervous System Disorders ; Peripheral Neuropathy ; Peripheral Nerves ; Production ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Recommendation ; Risk Factors ; Rodent ; Rodentia ; Rodents Mammals ; Safety ; Spinal Cord ; Medulla Spinalis ; Spinal Cord Diseases ; Spinal Cord Disorders ; myelopathy ; Streptozocin ; STZ ; Streptozotocin ; Zanosar ; Synapses ; Synaptic ; synapse ; Testing ; Time ; Tissues ; Body Tissues ; Translating ; Universities ; drebrins ; drebins ; Measures ; Synaptophysin ; Synaptic Vesicle P38 Membrane Protein ; Synaptic Vesicle Protein P38 ; Encephalopathies ; nerve injury ; neural injury ; Lysophosphatidic Acid Receptors ; LPA Receptors ; Peripheral ; Phase ; Histologic ; Histologically ; Physiological ; Physiologic ; Biochemical ; Evaluation ; nonhuman primate ; non-human primate ; diabetic ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Exposure to ; Morphology ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; neuropathic ; Neuropathy ; Spinal ; interest ; behavioral measure ; behavioral measurement ; behavior measurement ; Toxicities ; Toxic effect ; Structure ; novel ; Modeling ; Sampling ; Metabolic syndrome ; epigen ; Pathogenicity ; preventing ; prevent ; small molecule ; Absorption, Distribution, Metabolism, and Excretion Study ; ADME Study ; Data ; Process ; Enzyme Inhibition ; Development ; developmental ; Behavioral ; safety study ; preclinical study ; pre-clinical study ; glycemic control ; scale up ; drug distribution ; Impact evaluation ; diabetic rat ; Rat model of diabetes ; diabetic rat model ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; FDA approved ; effective therapy ; effective treatment ; preclinical efficacy ; pre-clinical efficacy ; screening ; behavioral study ; behavior study ; symptom treatment ; symptomatic treatment ; treat symptom ; High Fat Diet ; therapeutic candidate ; safety assessment ; Type 2 diabetic ; Type II diabetic ;