Novel Gut-Brain Drug Nezavist Shows Promise for Alcohol Use Disorder, Enters Phase 1 Trials
Key Insights
A novel drug called Nezavist targets gut-brain signaling via the vagus nerve (search) rather than acting directly on the brain, offering a new approach to treating alcohol use disorder (search).
In animal studies, Nezavist reduced the escalation of alcohol consumption following withdrawal in alcohol-dependent subjects, bringing intake back to baseline levels.
The drug appears to work by activating vagal pathways to reduce neuroinflammation, which is associated with negative feelings like anxiety and depression that drive relapse.
A novel drug developed by researchers at the University of Colorado Anschutz Medical Campus (search) may offer a fundamentally new approach to treating alcohol use disorder (search) (AUD) by targeting communication between the gut and brain rather than acting directly on the central nervous system. The experimental compound, called Nezavist, has demonstrated the ability to reduce the escalation of alcohol consumption that typically follows withdrawal in alcohol-dependent animal models, and is now being evaluated for safety in Phase 1 human clinical trials.
The drug originated from an idea by Boris Tabakoff, PhD, former chair of the Department of Pharmacology at the CU Anschutz School of Medicine and founder and CEO of Lohocla Research Corp. (search), who used rational drug design to synthesize a new molecule targeting pathways associated with alcohol use.
A Distinct Mechanism of Action
Unlike current pharmacological treatments for AUD — including naltrexone, acamprosate, and disulfiram — Nezavist does not appear to enter the brain. "What surprised us in our animal studies is that the drug does not appear to enter the brain. We barely see it in circulation because it is metabolized very rapidly," said Paula Hoffman, PhD, professor emerita in the Department of Pharmacology at the CU Anschutz School of Medicine. "These findings suggest that Nezavist could produce its effects through actions in the gut."
The drug appears to act in the intestine to activate the vagus nerve (search), which communicates with the brain and is involved in regulating inflammation. By activating specific vagal pathways, Nezavist can reduce neuroinflammation — a process increasingly implicated in excessive drinking and the development of AUD.
Recent research has provided evidence that chronic alcohol consumption and withdrawal can increase levels of immune signaling molecules in the brain, producing inflammation that is associated with negative emotional states such as anxiety, depression, and post-traumatic stress disorder. "If inflammation in the brain is involved in driving people to drink more alcohol, Nezavist, by activating normal vagal signaling pathways between gut and brain that lower inflammation, can reduce the relapse to alcohol consumption that occurs because of alcohol withdrawal," Hoffman explained.
Distinct from GLP-1 Drugs
Nezavist's mechanism also sets it apart from GLP-1 receptor agonists, which have garnered attention for their potential effects on alcohol consumption. "Rather than entering the brain, Nezavist acts only in the gut and activates normal body-to-brain communication pathways through the vagus nerve (search)," Hoffman noted. "Because it does not directly target reward systems in the brain as the GLP-1 drugs do, we hope it may avoid some of the neurological and psychiatric side effects that can occur when reward pathways are strongly suppressed, such as depression or anxiety."
Preclinical Findings
In animal models of chronic alcohol consumption, Nezavist consistently lowered the increased alcohol intake that occurs in alcohol-dependent animals after withdrawal when alcohol is again made available. The drug does not produce complete abstinence but brings consumption back to baseline levels, suggesting it may help stop the cycle of increasing alcohol intake after withdrawal.
The researchers have also investigated the drug's effects on nicotine, with similar results. "After nicotine is removed, animals increase their intake when it becomes available again. Nezavist prevents that escalation," Hoffman said. "Our findings suggest that neuroinflammation may be part of the process of alcohol relapse, and that reducing it can change behavior."
Safety Profile and Clinical Development
Preclinical safety studies have shown Nezavist to be well-tolerated overall. The main issue observed was some potential gastric irritation from a metabolite of the drug, similar to what can occur with aspirin or other nonsteroidal anti-inflammatory drugs. However, this was observed only at doses much higher than what is expected to be used therapeutically. "At the doses we anticipate using, we have not seen significant safety concerns," Hoffman stated.
The drug is currently undergoing single-dose safety studies in healthy volunteers. Multiple-dose safety studies, also part of Phase 1, will follow. If successful, the next step would be Phase 2 trials in people with alcohol use disorder (search), comparing the drug with placebo and beginning to evaluate effectiveness. Larger Phase 3 studies would follow positive Phase 2 results.
Future Directions
Beyond alcohol use disorder (search), the research team is interested in exploring whether this gut-brain approach could help with other addictions, including opioid addiction. "We are still at the beginning of understanding exactly how the drug works," Hoffman acknowledged. Key questions remain about which specific cells are affected, how they interact, and how those interactions ultimately change behavior. "Right now, our primary goal is to see whether the effects we observed in animals translate to humans."