Nezavist wordmark

Lohocla Development Pipeline

Preclinical
Discovery
Lead
Lead Optimization
Efficacy
in vitro
in vivo
Pharmacokinetics
in vitro
in vivo
Safety
in vitro
in vivo
IND
Phase I
Phase II
Nezavist®
Kindolor®
mol.BCUKA

Nezavist : Brief Summary

The National Institute on Alcohol Abuse and Alcoholism (NIAAA) describes, Alcohol Use Disorder (AUD) as a “chronic, relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational, or health consequences.” As of 2015, AUD affected 15.1 million adults and 623,000 adolescents in the U.S., and data from 2010 estimate an economic burden of $249 billion in the U.S. Globally, alcohol misuse was the fifth leading risk factor for premature death and disability in 2010.

Neurobiological hypotheses of AUD/alcohol addiction postulate that neuroadaptations occur in brain neurotransmitter systems that contribute to “craving” for alcohol, and relapse to drinking by dependent individuals who have stopped or reduced drinking for a period of time. Lohocla Research designed Nezavist to target these neuroadaptive changes and reduce relapse drinking. Lohocla has submitted an IND application to the FDA and plans first-in-human studies for the second half of 2022.

The research laboratories of the Lohocla leadership have contributed critical information to the understanding of the mechanisms by which alcohol affects behavior and the changes caused in brain by chronic alcohol ingestion that results in alcohol addiction. A discussion of this work can be found in a publication by Tabakoff and Hoffman in the journal Pharmacology, Biochemistry and Behavior.

Cartoon of microglia and their environment
Hyper-ramification of microglia resulting from chronic ethanol consumption
Microglial Hyper-ramification.
Hyper-ramification is the principal form of microglial activation in response to chronic alcohol consumption. Repeated cycles of drinking result in increasingly sensitized/activated hyper-ramified microglia, which contributes to the neurobiology of substance use disorders (adapted from F.T. Crews et al., 2017).

However, the most current research has demonstrated that a more holistic mechanism is responsible for human and other animal alcohol drinking behavior. Recent work shows that alcohol's actions in the gut may be the initial site that instigates the biologic changes that lead to AUD.

the vagus nerve and the gut-brain axis
The vagus nerve and the gut-brain axis.
The gut is the area of the body having the greatest concentration of immune cells as well as hormones controlling intake of caloric substances. The immune- and hormonal-systems of the gut communicate with the brain thereby affecting behavior. This gut-brain communication can occur by two paths: 1. by chemical signals traveling through the blood stream or 2. by signals carried along the vagus nerve, which creates a neuronal bridge between the gut and the brain. It has been proposed that ingested ethanol activates the immune system in the gut and inflammatory signals travel to the brain via the blood stream. Over time, these signals produce inflammation in brain tissue by activating cells called microglia. The inflammation in the brain leads to changes in brain chemistry that result in craving for alcohol leading to relapse in individuals trying to abstain.

Nezavist has been designed to break this cycle and reduce craving and relapse. Nezavist acts on the vagus nerve at the gut level to create neural signals that counter the inflammation caused in the gut and the brain by the chronic consumption of alcohol. Nezavist changes the pattern of vagal-nerve signaling to the brain and vagal signals have been shown to suppress the microglial inflammatory state, thus reducing the craving for alcohol, supporting the maintenance of healthy brain tissue, and aiding abstinence.