How is Nezavist different from current pharmacological treatments for alcohol use disorder?
Current pharmacological treatments for alcohol use disorder include naltrexone, an opioid receptor antagonist that helps to reduce the urge to drink alcohol and maintain abstinence. Acamprosate also helps maintain abstinence. These drugs can be effective, but only a small percentage of individuals with AUD receive treatment. Disulfiram (Antabuse) is another treatment option that causes unpleasant reactions when alcohol is consumed. It helps to discourage drinking, but this drug is not effective without supervision.
Nezavist is being developed to help prevent relapse and escalation of alcohol consumption after alcohol withdrawal. In our testing of animal models with chronic alcohol consumption (dependence), alcohol intake increases dramatically when alcohol is removed and then again made available. Nezavist prevents that escalation. Nezavist does not produce complete abstinence. But it brings consumption back to baseline, suggesting it may help stop the cycle of increasing alcohol intake after withdrawal.
How does Nezavist work?
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. These findings suggest that Nezavist could produce its effects through actions in the gut. Our animal studies showed that Nezavist acts in the intestine to activate the vagus nerve. The vagus nerve communicates with the brain and is involved, among other things, in regulating inflammation. By activating specific vagal pathways, the drug can reduce brain inflammation.
Can reducing neuroinflammation help treat alcohol use disorder?
Recent research has provided evidence that chronic alcohol consumption and withdrawal can increase the levels of immune signaling molecules in the brain and produce inflammation in the brain. This neuroinflammation is also associated with negative feelings such as anxiety, depression and post-traumatic stress disorder.
The evidence suggests that brain inflammation and these negative feelings play an important role in excessive drinking and can lead to development of AUD. Neuroinflammation also plays a role in withdrawal and the vulnerability to relapse. 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.
How was Nezavist discovered?
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. Tabakoff used rational drug design to synthesize a new molecule that would affect targets associated with alcohol use.
We initially tested the new molecule in models of alcohol withdrawal and later began studying its effects on alcohol-seeking behavior after withdrawal, which became the major focus for Nezavist.
What have studies of Nezavist shown so far?
Nezavist consistently lowered the increased alcohol intake that occurs in alcohol-dependent animals after withdrawal when alcohol is again made available. We have also looked at nicotine, and the drug appears to have similar effects. After nicotine is removed, animals increase their intake when it becomes available again. Nezavist prevents that escalation.
Our findings suggest that neuroinflammation may be part of the process of alcohol relapse, and that reducing it can change behavior. So far, alcohol and nicotine are the substances we have studied most extensively.
What makes Nezavist different from GLP-1 drugs and other brain-targeting treatments?
Nezavist appears to work differently than drugs such as GLP-1s that enter the brain and act on receptors involved in the reward system to reduce 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. In that sense, it is using systems the body already relies on to regulate brain processes, including inflammation.
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. We are essentially using the body's normal signaling systems rather than directly acting on the brain itself.
What have the safety studies found?
So far, Nezavist appears to be very safe. We are currently conducting phase 1 clinical trials in healthy volunteers to evaluate safety.
The main issue we have seen in preclinical studies is some potential gastric irritation from a metabolite of the drug, similar to what can occur with aspirin or other nonsteroidal anti-inflammatory drugs. That was observed only at doses much higher than what we expect to use therapeutically. At the doses we anticipate using, we have not seen significant safety concerns.
Where does the clinical development process stand today?
We are currently conducting single-dose safety studies in healthy volunteers. After that, we will need multiple-dose safety studies, which are also part of phase 1.
If those studies are successful, the next step would be phase 2 trials in people with alcohol use disorder. Those studies compare the drug with a placebo and begin evaluating effectiveness. If effective, larger phase 3 studies would follow. At this point, our focus is on establishing safety and then determining whether the drug is effective for people.
What are the next questions you hope to answer?
We would like to know whether this approach could help with other addictions, including opioid addiction. We are still at the beginning of understanding exactly how the drug works.
Our research has helped us build a proposed pathway involving the gut, the vagus nerve and neuroinflammation, but there is still much to learn. Which cells are affected? How do they interact? How do those interactions change behavior?
Right now, our primary goal is to see whether the effects we observed in animals translate to humans.
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