A New Therapy For Alcohol Abuse?

 BY DEREK LOWE

A couple of years ago I wrote about a PDE4 inhibitor, apremilast, and the multiple process chemistry routes that have been used to prepare it. apremilast is approved for use in various autoimmune inflammatory disorders, but PDE enzyme subtypes are involved in a huge number of cellular processes, so a PDE inhibitor is never going to do just one thing.

For example, PDE4 (specifically PDE4b) has also been linked to possible benefits in drug abuse patients. It’s believed that a cAMP signaling pathway in the forebrain becomes upregulated after long-term addiction, and that an inhibitor like this could therapeutically disrupt that adaptation. PDE4 inhibitors have been studied in models of cocaine and heroin abuse, and I have to say that if you can interrupt those, you can probably interrupt most anything. It’s also shown effects on alcohol preference and consumption in rodent models

Here’s a review of apremilast and its effects on alcohol consumption in humans. There was already some expectation that this effect would translate, since a genome-wide association study (GWAS) in the UK Biobank had come up with mutations in the PDE4b gene (among other things) as associated with alcohol use. This new paper reports a Phase IIa clinical study in 51 male and femaile volunteers with greater-than-moderate alcohol use disorder (as defined by the DSM). These were randomized into a 90mg-daily apremilast group and a placebo group over an 11-day period, and there appears to have been a significant effect in the apremilast group as compared to the controls, with fewer drinks per day and a lower probability of having a day of heavy drinking, along with subjective reports of less craving for alcohol. There seems to have been no rebound effect during the two week post-study followup.

This isn’t a large study, but it certainly suggests that followup is warranted, given the general weight of the evidence and the consistency of the clinical effect. It will certainly be worth seeing how well this effect holds up in a larger group, and whether any particular patient subtype groups show smaller or larger effects. Given that the drug is already FDA-approved and has been on the market for many years now, this might well be one of the rare examples of a drug repurposing effort that comes through - and given the toll of alcohol addiction in the general population, it’s coming through in a very useful area.

https://www.science.org/content/blog-post/new-therapy-alcohol-abuse