Development of a Novel Medication for Alcohol Use Disorder with an Active IND Dual Inhibitor of T-Type Calcium Channel and Soluble Epoxide Hydrolase - 7. SUMMARY
Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide and often co-occurs with
chronic pain, anxiety, depression, and opioid dependence. Unfortunately, currently available medications for
AUD have limited efficacy with unwanted side effects. To address this unmet medical need, we propose an SBIR
Phase I U43 project in response to PAR-22-102 "Investigational New Drug (IND)-enabling and Early-Stage
Development of Medications to Treat Alcohol Use Disorder and Alcohol-Associated Organ Damage." Our project
will focus on proof-of-concept studies of our active IND (157314), AFA-281, a novel dual inhibitor of T-type
calcium channels (Cav3) and soluble epoxide hydrolase (sEH), for AUD treatment. These proof-of-concept
studies would use well-established rodent AUD models and testing paradigms.
AfaSci discovered AFA-281 from a series of patented dual modulators of Cav3 channels and sEH as a non-
opioid analgesic. We completed lead identification through rational drug design and iterative screenings using
patch-clamp recordings and enzymatic assays. Lead optimization was conducted, including selectivity screening
on hERG and key cardiac ion channels, and CEREP proofing of 81 off-drug targets. These screenings together
with studies using human cardiomyocytes ex vitro demonstrated that AFA-281 has no cardiac safety concerns.
In pharmacokinetic and pharmacodynamic (PK/PD) studies, AFA-281 has shown excellent oral bioavailability,
acceptable t1/2, CNS penetration, broad analgesic effects on neuropathic and inflammatory pain, and good safety
margins. Recently, AFA-281's IND application was accepted by the FDA for a lead indication of neuropathic pain.
Our preliminary studies on AUD have demonstrated that AFA-281 is capable of decreasing alcohol intake, binge
drinking and preference, and suppressing alcohol-seeking behavior in rodents.
In this proposed SBIR Phase I U43 project, we will conduct preclinical proof-of-concept studies to investigate
AFA-281's effects on AUD, and its associated chronic pain and negative affective disorders, such as anxiety and
depression in rats via three Specific Aims. Aim 1 will evaluate PK/PD of AFA-281 in reducing alcohol consuming
and seeking behavior via operant self-administration. Aim 2 will investigate AFA-281's effects on hyperalgesia,
anxiety, and depression in rats withdrawn from chronic alcohol consumption. Aim 3 will explore the mechanism
of action of AFA-281 underlying its efficacy in AUD via assessing AFA-281’s modulation on alcohol-altered neural
activity indicated by c-Fos expression and brain neuroinflammation, and evaluation of Cav3 channel activity, and
cell excitability in the lateral habenula, a brain area implicated in AUD.
Success in our Phase I project would demonstrate that AFA-281 can reduce alcohol consumption and seeking
behavior, provide an evidence base to prepare for the transition to clinical proof-of-concept studies in the U44
SBIR project. Given the significant public health burden of AUD, developing a more effective and safe medication
accessible for treatment and prevention of AUD would have a considerable positive impact on public health.
