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.
