MRC AZ CLD 2018

Lead Research Organisation: University of Oxford

Abstract

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Technical Summary

Deficits in impulse control are prominent in a diversity of psychiatric illnesses including bipolar and related mood disorders, and strongly associated with suicidality, relapse to drug-seeking behaviour and pathological gambling. Drug therapies of impulsivity are few, and those available are poorly tolerated as exemplified by lithium. Lithium is the mainstay therapy for bipolar disorder and reduces risk of suicide, but is poorly tolerated and has severe side-effects including renal damage. All this makes a compelling case to develop new impulsivity lowering drugs that have the unique therapeutic profile of lithium without its adverse effects. A leading idea for lithium's mechanism is inhibition of inositol monophosphatase (IMPase), causing reduced transmitter signalling via the phosphoinositide pathway. Recently, we "reprofiled" a library of clinically used drugs and identified an IMPase inhibitor, ebselen, which is an organoselenium compound originally developed as an antioxidant. Ebselen is non-selective and its IMPase action requires selenium, which severely limits chemical optimisation to both improve selectivity and potency, and allow commercial exploitation. However, as ebselen is safe in man it has potential for fast-tracking to clinical trial. With MRC DPFS funding we have established a developmental pathway and progressed ebselen from preclinical studies and experimental medicine models predictive of efficacy and target engagement, through to imminent clinical trials in bipolar disorder. We are now well-positioned to advance through this pipeline the next generation inhibitors of IMPase that have greater selectivity and potency than ebselen, and greater asset (IP) value. The support of the MRC/AZ CLD to target IMPase, combined with our drug development pipeline, will accelerate the clinical development of this new generation of IMPase inhibitors as safe lithium-mimetics for the treatment of patients characterised by poor impulse control.

Planned Impact

A common account of impulsivity is 'actions that are poorly conceived, prematurely expressed, unduly risky, or inappropriate to the situation and that often result in undesirable outcomes'. A healthy level of impulsivity can be beneficial (eg. to seize opportunities and gain valuable new experiences) but high levels of impulsivity are often socially unacceptable and can be personally and financially costly. Moreover, deficits in impulse control are a prominent feature of diverse psychiatric illnesses including bipolar and related mood disorders, addictions and impulse conduct disorders (ICDs). Impulsivity is also strongly associated with suicidality and relapse to drug-seeking behaviour, and is a significant predictor of relapse and worse clinical outcomes in alcohol and substance dependence, and pathological gambling. Drug therapies of impulsivity are few, and those available are poorly tolerated as exemplified by lithium. Lithium is the mainstay therapy for bipolar disorder, reduces risk of suicide, and is effective in clinical trials of ICDs such as pathological gambling. Despite its significant benefits lithium is poorly tolerated, and has severe side-effects including kidney damage. All this makes a compelling case to develop alternative drugs to control impulsivity. The solution may be a drug that has the unique therapeutic profile of lithium without its adverse effects. Lithium's mechanism is unclear but a leading idea is inhibition of the enzyme inositol monophosphatase (IMPase), causing reduced transmitter signalling via the phosphoinositide (PI) pathway.

Recently, we identified an IMPase inhibitor, ebselen, that is non-selective and has unusual molecular structure that limits opportunities for both chemical optimisation of the drug to improve selectivity and potency, and commercial exploitation. However, because ebselen is proven safe and tolerated in humans, it has the potential for fast-tracking to clinical trial and therapeutic application. With MRC DPFS funding ourselves and our clinical collaborators have established a translational developmental pathway in which ebselen has progressed from preclinical studies and experimental medicine models predictive of efficacy and target engagement, though to clinical trials in bipolar disorder which are about to commence. We are now well-positioned to advance through this pipeline the next generation inhibitors of IMPase that have greater selectivity and potency than ebselen, and with more significant asset (IP) value. The combination of the MRC/AZ Centre of Lead Discovery to target IMPase with our drug development pipeline would accelerate the clinical development of this next generation of IMPase inhibitors as safe and tolerated lithium-mimetics for the treatment of patient groups characterised by poor impulse control.

Publications

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