Proof of concept: diclofenac as a KMO inhibitor in AUD

Summary The development of efficacious medications for AUD remains a high research priority with current emphases on identifying novel molecular targets and efficiently screening new compounds. Pharmacological modulation of the kynurenine pathway (KP) represents a promising novel target for AUD. The KP is a complex enzymatic cascade with each step producing biologically active metabolites that are critically involved in diverse physiological and pathological processes. Chronic alcohol exposure produces dysregulation of the KP, particularly as evidenced by decreased levels of the neuroprotective metabolite kynurenic acid (KYNA) and increased levels of the neurotoxic metabolite quinolinic acid (QUIN). This metabolic shift is associated with various alcohol-related pathologies in animals and humans. Thus, a medication that targets the KP to restore KYNA and attenuate QUIN levels may be an effective treatment for AUD. The enzyme kynurenine 3-monooxygenase (KMO) is a major gatekeeper of the KP and resultant KYNA levels. KMO inhibition shifts the KP towards KYNA production in brain and away from QUIN production. Critically, KMO inhibition in rodents, through its increase in brain KYNA levels, decreases alcohol self-administration, preference, cue-reactivity, and relapse behaviors. However, KMO-inhibitors have not been tested in humans because of presumed lack of availability. Diclofenac is an FDA-approved Non-Steroidal Anti-Inflammatory Drug that was recently discovered to inhibit KMO activity. Consistent with KMO inhibition, diclofenac increases KYNA levels in the brain and periphery of rodents. However, it remains unknown whether diclofenac increases KYNA levels and affects alcohol-related behaviors in humans at approved, safe dosages. In a Phase Ia/b proof of concept study, we will test the pharmacological mechanism, optimal dosing, tolerability, and initial efficacy of diclofenac as a potential novel treatment for AUD. We will conduct a randomized, double-blind, dose-escalating, placebo-controlled, cross-over study in which individuals with AUD (n=24) complete four sessions where they receive diclofenac (25 mg, 50 mg, or 75 mg) or placebo. Our primary aim is to identify the dose by which diclofenac, vs. placebo, produces changes to the KP indicative of KMO inhibition (e.g., increasing KYNA levels). We will also assess whether diclofenac, vs. placebo, decreases tonic alcohol craving and negative mood, attenuates alcohol cue-reactivity, and improves cognitive function. Findings will inform subsequent studies testing diclofenac for AUD as well as other disorders for which KMO inhibition has been identified as a pharmacological target of interest.