SBIR-STTR Award

Funding Opportunity: PA-18-574 - PI Name: Mamet, Julien As described by the HEAL Initiative Notice NOT-NS-19-014, there currently exists an urgent unmet need for enhanced pain management in the form of safe, effective, non-opioid pain treatments. Chronic focal neuropathic pain, which includes pain etiologies such as radiculopathy and radiculitis1-3, focal peripheral neuropathies4, and low back pain5, affects as many as 25 million patients annually in the United States. These conditions are commonly treated with opioid analgesics, with some patients subsequently experiencing addiction and abuse. Chronic focal neuropathic pain is maintained by genome-wide transcription regulation in the dorsal root ganglia (DRG) / spinal cord network. The transcription factors driving this regulation constitute a promising class of targets with the potential to alter the course of pain with a single treatment. DNA decoys are oligonucleotides that specifically inhibit the activity of certain transcription factors. Following advancement of Adynxx’s lead decoy program, brivoligide (formerly AYX1) the for treatment postoperative pain, into Phase 2 clinical studies, Adynxx began development of its second decoy AYX2 for altering the course of chronic pain. AYX2 binds and inhibits Krüppel-like transcription factors (KLF) 6, 9 and 15 in the DRG-spinal cord. In the Spared Nerve Injury and Chronic Constriction Injury rat models of chronic pain, a single intrathecal (IT) injection of AYX2 produces a substantial, weeks-long reduction of pain compared to controls.6 The goal of this Phase 1 proposal is to advance AYX2 toward an IND submission, allowing for human clinical trials. We propose in Aim 1 to characterize AYX2 pharmacokinetics in the cerebrospinal fluid and plasma and its distribution in the DRG, spinal cord and brain following an IT injection. With this information, AYX2 will be tested in a panel of complementary toxicology studies in Aim 2 to allow for final IND-enabling studies, supported by Phase 2 of the grant. This research will accelerate development of AYX2 as a novel drug candidate for the non-opioid treatment of pain.

Public Health Relevance Statement:
RESEARCH AND RELATED OTHER PROJECT INFORMATION – PROJECT NARRATIVE Funding Opportunity: PA-18-574 - PI Name: Mamet, Julien Adynxx is currently developing a DNA decoy drug candidate, brivoligide, which blocks the action of a transcription factor that is essential for the development of exacerbated pain after surgery, and which has reduced postoperative pain and opioid use in clinical trials conducted to date in a population of medically underserved patients. This grant application seeks to support preclinical work needed to advance AYX2, a new DNA decoy drug candidate for the safe and long-term treatment of chronic pain which blocks the action of transcription factors that are essential for the maintenance of chronic pain, into clinical stage studies. Preclinical work performed to date indicates that a single intrathecal injection of AYX2 should safely provide months of pain relief while minimizing the need for opioids in patients, in alignment with a recently announced interest of the HEAL initiative.

NIH Spending Category:
Chronic Pain; Genetics; Neurodegenerative; Neurosciences; Opioids; Pain Research; Peripheral Neuropathy

Project Terms:
addiction; Adverse event; Affect; Applications Grants; Automobile Driving; Back; Binding; Biological Assay; Blinded; Blood capillaries; Brain; Canis familiaris; Cerebrospinal Fluid; Chromosome abnormality; Chronic; chronic constriction injury; chronic neuropathic pain; chronic pain; Clinic; Clinical; Clinical Pathology; Clinical Research; Clinical Trials; Conduct Clinical Trials; design; Detection; Development; Disease; DNA; Dose; drug candidate; Drug Kinetics; efficacy testing; Etiology; experience; Formulation; Funding Opportunities; gel electrophoresis; genome-wide; genotoxicity; Goals; Grant; Histopathology; Human; Hypersensitivity; in vivo; interest; Intrathecal Injections; knee replacement arthroplasty; Kruppel-like transcription factors; Laboratories; Lead; Maintenance; Mechanics; medically underserved population; Microscopy; Modeling; Names; nerve injury; non-opioid analgesic; novel therapeutics; Oligonucleotides; Operative Surgical Procedures; Opioid; Opioid Analgesics; opioid use; Pain; Pain management; pain model; pain reduction; pain relief; painful neuropathy; patient population; Patients; Pattern; Peripheral; Phase; Plasma; Postoperative Pain; pre-clinical; programs; Publishing; Radiculopathy; Rattus; Regulation; Research; response; screening; spared nerve; Spinal Cord; Spinal Ganglia; Syndrome; Testing; Tissues; Toxicology; transcription factor; Transcriptional Regulation; United States;