R44NS132642

Clinical Phase I trials on an IND single molecule dual inhibitor of CAV3 channels and soluble epoxide hydrolase for treatment of neuropathic pain - 7. Project Summary

We propose conducting clinical Phase I trials on an active IND (157314), AFA-281, a non-opioid, single small molecule that inhibits both T-type CAV3 calcium channels and soluble epoxide hydrolase (SEH) to treat chronic neuropathic pain.

Millions of Americans suffer from chronic pain, especially neuropathic and inflammatory types. Yet less than 50% of patients respond to current treatments, leading to increased reliance on opioids. There is strong rationale to target CAV3 and SEH jointly.

Tissue and nerve injury trigger inflammation, which increases neuronal hyperexcitability. This increases activation of the CAV3.2 channel subtype in the sensory nervous system, exacerbating pain and touch sensitivity. CAV3.2 upregulation and overactivation were observed in human patients with chemotherapy-induced neuropathic pain, irritable bowel syndrome (IBS), and osteoarthritis (OA), with similar findings in animals.

In addition, SEH breaks down the body's anti-inflammatory mediators, epoxy-fatty acids (EPFAs), into inflammatory diols. SEH is involved in inflammatory OA pain and IBS visceral pain in humans. Single SEH inhibitors mitigate inflammatory and neuropathic pain in animals. Therefore, a single drug inhibiting both CAV3.2 and SEH could produce complementary analgesia and anti-inflammatory effects.

As a dual-inhibitor fitting this profile, AFA-281 could improve the patient experience by reducing polypharmacy, pill burden, medication nonadherence, dose-limiting side effects, and drug-drug interactions. AFA-281 potently inhibits both CAV3.2 and SEH, whereas it causes 50- to 500-fold weaker inhibition against 81 off-targets tested. AFA-281 produces significant analgesia and reduction of brain microglia activation in a neuropathic pain model of spared nerve injury (SNI) in rats.

GLP safety pharmacology, toxicity, and genotoxicity studies indicate AFA-281 has no cardiac toxicity concerns and is a safe drug meriting first-in-human studies. The FDA thoroughly reviewed our IND application and determined "IND 157314 study may proceed" on November 11, 2022. Therefore, we propose conducting clinical Phase I trials with three specific aims:

Aim 1. Phase I Part 1: A double-blind, placebo-controlled study of single ascending doses (SAD) of oral AFA-281 in healthy volunteers will investigate the safety, tolerability, and pharmacokinetics (PK) of AFA-281.

Aim 2. Phase I Part 2: A double-blind, placebo-controlled study of multiple ascending doses (MAD) of oral AFA-281 in healthy volunteers will characterize the safety and PK for up to 14 days of dosing.

Aim 3. Explore target engagement during the Part 2 MAD trial. In vivo SEH inhibition will be measured by plasma EPFA/diol ratio increases. Electroencephalogram/electromyography (EEG/EMG) will be used to assess CAV3 channel engagement, as EEG changes by a CAV3 blocker have been reported in human and rodent EEG.

Phase I trial success by achieving the primary safety objective can advance AFA-281 to proof-of-concept studies on neuropathic pain in Phase II trials. Ultimately, an effective and safe, non-opioid, non-NSAID, and non-addictive analgesic will provide an alternative for neuropathic pain treatment and help end the opioid crisis.

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(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

Redwood City, California 940633848 United States

Single Zip Code

Administrative Supplements to Existing NIH Grants and Cooperative Agreements (Parent Admin Supp Clinical Trial Optional) (PA-20-272)

Amendment Since initial award the total obligations have increased 103% from $1,499,931 to $3,049,862.