PROJECT 1: Phase 2a dose-response study of apremilast in females and males with alcohol use disorder

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

PROJECT 1 ABSTRACT Rates of alcohol use disorder and high-risk drinking continue to increase in women, leading to greater alcohol-related pathology and consequences, including recent and concerning increases in alcohol-related mortality. We identify that drinking behavior in women is more likely to be motivated by affect regulation and stress, whereas drinking in men is motivated by stimulation and alcohol-related positive reinforcement. Across the Yale-SCORE, we are developing therapeutics to treat alcohol use disorder (AUD), with a focus on the ‘dark side of addiction’ (i.e., targeting stress and negative affect). Our robust data generated over the last funding cycle, has identified key sex-differences leading to successful treatments for females with AUD, supporting our continued focus on negative reinforcement drinking for medication development. For our renewal, Project 1 will focus on neuroimmune function as a medication target. This decision is based on exciting findings from Project 2, documenting a bigger deficit in a marker of microglia in females with AUD compared to men with AUD, suggesting greater neuroimmune dysfunction in females. Microglia are the immune cells of the brain and are tasked with maintaining healthy brain function. Stress and alcohol disrupt the healthy immune environment leading to a cascade of brain changes that ultimately may drive continued drinking and increase negative affect. Project 1 will translate these findings and examine PDE4 as a neuroimmune target for AUD treatment. PDE4 inhibition is known to attenuate stress-precipitated drinking and alcohol-related positive reinforcement. We hypothesize that targeting PDE4 inhibition (with apremilast) for AUD treatment may be effective across sex, with larger effects in females, and that benefits will operate through sex-dependent mechanisms. Our robust pilot data demonstrate that apremilast is well tolerated and reduces alcohol consumption with large effects. Consistent with the aim of the Yale-SCORE, we plan to conduct a double-blind, placebo-controlled, dose-response, parallel-group mechanistic Phase 2a study to examine sex differences in apremilast’s effect on 1) counteracting stress- and stimulation-based drinking behavior in the laboratory and 2) reducing naturalistic drinking behavior in females and males with AUD. Importantly, in concert with Projects 2 and 3, we will identify sex differences in neuroimmune mechanisms underlying drinking. To our knowledge, this will be the first fully powered investigation to prospectively examine sex differences in the therapeutic potential and associated mechanisms of apremilast for the treatment of AUD. Positive findings will identify which doses of apremilast demonstrate efficacy for reducing alcohol consumption while minimizing adverse events in females and males with AUD, and provide the data necessary to inform and expand this investigation to a Phase 2b clinical treatment trial for AUD.