A clinical trial carried out at Scripps Research has shown that apremilast, approved by the U.S. Food and Drug Administration (FDA) for the treatment of psoriasis, cuts alcohol intake by more than half in people with severe alcohol use disorder (AUD). Collaborators at Oregon Health and Science University (OHSU) and other institutionsalso showed that, in mice, apremilast boosts activity in an area of the brain known to be involved in AUD.
The research was published online ahead of print by theJournal of Clinical Investigation on January 19, 2023.
“We’re incredibly excited to have found a drug that has such a large effect size on alcohol consumption, and with such good tolerability and safety at the same time,” says co-senior author Barbara Mason, PhD, the Pearson Family Chair and Director of the Pearson Center for Alcohol and Addiction Research at Scripps Research.
About 29.5 million Americans meet the criteria for AUD, which encompasses the conditions known as alcohol abuse, alcohol dependence and alcohol addiction. Fewer than 10% of people with the disorder get any treatment, and an even smaller number are prescribed medication to treat AUD.
Mason is the director of the Translational Opportunities group for the Integrative Neuroscience Initiative on Alcoholism-NeuroImmune (INIA-NeuroImmune), a multidisciplinary, collaborative consortium funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) to study the underlying biology of alcohol use disorder. In her role with INIA-NeuroImmune, Mason reviews research conducted by basic scientists in the consortium, and then identifies the most promising drug candidates for clinical trials.
INIA-NeuroImmune collaborators pinpointed apremilast — sold under the brand name Otezla® — as a drug with the potential to treat AUD. The drug was known to block a molecule known as PDE4, which plays important roles in both immune and brain cell function. While its use in treating psoriasis is due to its immune function, basic scientific studies in mice had suggested that blocking PDE4 in the brain could reduce alcohol intake.
Mason launched a phase 2 trial, carried out entirely at the Pearson Center for Alcoholism and Addiction Research at Scripps Research, to study apremilast in humans. Among available PDE4 inhibitor medications, Mason chose apremilast because it had fewer of the gastrointestinal side effects associated with earlier PDE4 inhibitors such as rolipram or ibudalast. The trial enrolled 51 paid adult volunteers with severe AUD, none of whom were actively trying to consume less alcohol. For 14 days, each person took a daily pill of either apremilast or a placebo.
On average, participants consumed about five alcoholic drinks per day at the start of the study. People who received the placebo still drank nearly five drinks each day, while those who took apremilast reduced their alcohol intake to only about two drinks per day. In addition, apremilast decreased the percent of days that participants were classified as “heavy drinkers.” People who took apremilast reported anecdotally that they felt little impulse to drink and lacked the desire for alcohol that they usually had. Moreover, the drug was well tolerated with no participants discontinuing treatment due to gastrointestinal side effects.
“In this study, we saw that apremilast worked in mice. It worked in different labs, and it worked in people. This is incredibly promising for treatment of addiction in general,” says co-senior author Angela Ozburn, PhD, associate professor of behavioral neuroscience in the OHSU School of Medicine and a research biologist with the Portland VA Health Care System.
“Even with drugs currently approved by the FDA for alcohol use disorder, we usually see smaller effect sizes,” says Mason. “It’s very unusual to get results like this, particularly in a severely affected population. This will need to move to larger, broader clinical trials now, but with this study, I think we’ve shown that this is an incredibly promising drug for alcohol use disorder.”
In addition to Mason and Ozburn, authors of the study, “Pre-clinical and clinical evidence for suppression of alcohol intake by apremilast,” are Alan Beneze, Jessica Bess, Jenny Miller, Susan Quello, Amanda J. Roberts, Marisa Roberto, Farhad Shadan and Michael Skinner of Scripps Research; John C. Crabbe, Evan J. Firsick, Kolter B. Grigsby, Pamela Metten and Kayla G. Townsley of Oregon Health & Science University; Heather C. Aziz, Regina A. Mangieri and Richard A. Morrisett of The University of Texas at Austin; Howard C. Becker and Marcelo F. Lopez of Medical University of South Carolina; Toby K. Eisenstein and Joseph J. Meissler of Temple University; and John M. Light of Oregon Research Institute.
This work was supported by funding from the National Institutes of Health (AA016651, AA013519, AA010760, AA07468, and AA027692, U01 AA013498, DA013429, P60AA06420 U01AA025476); the US Department of Veterans Affairs Grants (BX000313, BX004699, and IK2 BX002488), and a gift from the John R. Andrews Family.