Evaluation of the central effects of a delta opioid agonist on biomarkers of efficacy in anxiety and depression

Most drugs for mental illness which look promising and novel in the laboratory, fail to reach the bedside. This is generally because they do not work when they are tested in large and very expensive clinical studies in patients for which the drug is intended. Increasingly, the financial risk of failure is seen as generally too great to maintain the major infrastructure necessary for development. Several companies have closed down their development programs even though they have novel drugs which show promise. These drugs are often very well characterised with highly selective actions on specific neurotransmitter systems. They are therefore of great interest to the scientific community as tools to understand the role of neurotransmitters in mental illnesses. Furthermore, the community has the expertise and capacity to take on some of the clinical development, especially when targeted at identifiable subgroups within a disorder.

One approach to de-risking development is to attempt to detect efficacy early in clinical development, even in healthy volunteers, using tests of brain functioning (biomarkers) that probe relevant actions of drugs. The applicants are known to Industry and Academia for their development of biomarkers for CNS processes that underpin anxiety and depression. The biomarkers are based on measuring people's automatic and usually unconscious responses to mildly emotional images of faces or scenes that evoke little or no emotion in the viewer. The measures typically involve reaction times, accuracy or automatic memorising. Importantly, the responses of brain systems can also be visualised and quantified using functional magnetic resonance imaging (fMRI). Studies using these measures suggest that the risk of depression is associated with an unconscious tendency to automatically attend to, and process negative information in the world and about themselves. Remarkably, antidepressant drugs can shift biases in a positive direction even in people with no risk of depression and without affecting mood. Some of the most efficient measures at detecting drug effects have been collated into the Emotional Test Battery (ETB).

This proposal is to rescue a drug (AZD7268), which has well-defined actions at the delta opioid receptor (DOR), from the closed AstraZeneca psychiatry program. The DOR detects and transmits the effects of endorphins in the brain called enkephalins. AZD7268 mimics the effects of enkephalins in stimulating the DOR. Preclinical and clinical data suggested that AZD7268 would be effective in depressive illnesses associated with high levels of anxiety. The DOR is located specifically in regions of the brain such as the amygdala and hippocampus that mediate behavioural effects of stress in animals and its subjective effects in humans. Genetically modified mice made to lack the DOR or to lack enkephalin show behavioural characteristics of fearfulness and depression (learned helplessness) and DOR drugs such as AZD7268 have the opposite effect.

In a clinical trial in 247 patients, AZD7268 was effective in reducing depression compared to placebo only in the predicted anxious-depressed group and not in depression without marked anxiety. We aim to build confidence in this finding by using the ETB to profile the effects of AZD72688 on performance and brain imaging measures of psychological tasks that assess reward, punishment and emotion processing in a non-clinical sample of volunteers. Half the volunteers will be selected for high levels of anxiety and depression using standard self-rating questionnaires. Robust effects of AZD7268 on the ETB would suggest that DORs have at least a modulatory role in the causation of anxiety and depression that is worth pursuing therapeutically in a joint development programme between the MRC and AstraZeneca.

This is a double-blind randomised placebo-controlled study of a delta opioid receptor agonist (AZD7268) in 64 physically healthy volunteers. Participants will be stratified according to high (n=32) or low scores (n=32) on the self-rated Beck Depression Inventory. Spielberger Trait Anxiety ratings will be a covariate in the analysis. Half of each group will be randomised to receive placebo and half AZD7268. The design is a 2x2 factorial design with a drug-treatment factor (placebo vs AZD7268) and a clinical grouping factor (low vs high anxious-dysphoria). Half the sample will be recruited in Manchester and half in Oxford.

After 7 days of treatment, participants will attend research facilities on day 8 for interview and self-rating assessments, fMRI emotional processing tasks followed by completion of the Emotional Test Battery. The design is similar to our recently completed stratified study of the effects of escitalopram vs placebo in 240 dysphoric and non-dysphoric participants gathered across 3 centres over a period of 13mths. This will provide very useful comparative data for the effects of AZD7268.

All tests have been selected because they show sensitivity to anxiolytic or antidepressant treatment.

FMRI tasks: i) Facial Emotion Processing; ii) Emotional Counting Stroop; iii) Monetary Incentive Delay task; iv) Visual Checkerboard.

The Emotional Test Battery comprises: (i) Facial Expression Recognition Task- accuracy of perception of emotion in faces (eg fear, happiness); (ii) Emotional Categorisation Task (ECAT)- reaction time to negative versus positive personality characteristics; iii) Emotional Recognition Memory Task - recall of items on the ECAT; (iv) Dot-probe - measures automatic attention to emotionally valenced visual stimuli; v) Emotion Potentiated Startle Task - exaggeration of startle responses by prior presentation of emotional images.

Data analysis by ANCOVAR with main effects and interactions of treatment and group

We have noted in a previous section, the clinical benefit that would flow from a new treatment for a difficult to treat subgroups of patients with depression who are prone to treatment resistance and thus chronicity. However, in addition to addressing an area of high unmet medical need and disease burden, the development of a new treatment is also anticipated to have considerable economic impact by reducing the number of lost days at work, reducing healthcare and social costs and reducing the impact on families.

Confirmation of the therapeutic potential of delta opiate receptor agonists in the treatment of depressive illness would provide a major advance in our scientific knowledge. Current treatments for depression are based on modulation of monoamine neurotransmitters and no new neurobiological principle of treatment has been established. However, if activating the delta opiate receptor modulates abnormal stress responses, then continued mechanistic studies could generate other new approaches to treatment within the stress-response pathway. Furthermore, a positive outcome from the proposed study would stimulate a new research area in the pathogenesis of depression. Dissemination of the outcome of the proposed study alone is anticipated to elicit considerable scientific interest and activity.

Recently, the pharmaceutical industry has reduced its efforts in developing new treatments for neuropsychiatric disorders. One of the main drivers for this is the lack of advances in understanding the neurobiology of psychiatric disorders. This in turn reduces the number of potential drug targets with the potential to bring improvement over existing treatments. It is striking that the broad range of current neuropsychiatric drugs is based on a handful of well-established targets. Therefore, identification of a new therapeutic mechanism is likely to stimulate broad interest in drug development and reinvestment in this area.

The proposed collaboration between academic laboratories, an SME and a large pharmaceutical industry partner with Medical Research Council support would set an important precedent for ways in which industry, academia and governments can work together to bring new treatments to patients. We will gain first-hand experience of how such collaborations can operate successfully and we intend to publish insights into the functioning and potential improvement of collaborations as well as the results of the research program.

If the current study confirms the potential of AZD7268, AZ and the investigators will explore a number of options to develop the drug for regulatory approval. Such a development program will require several large-scale pivotal efficacy and long-term safety studies and we will explore options for innovative collaborative approaches. This could lead to new ways in which academia and industry work together with the NHS. There is a growing realisation that the NHS is a globally unique resource for clinical research because it treats the vast majority of the nation's patients. A major shift is occurring in the attitudes and organisation of research in the NHS along with a sharp increase in its funding. These factors and the formation of Clinical Research Networks, explicitly to provide a R&D infrastructure for UK industry, set the stage for an era of enterprise in drug development in the NHS that is timely and propitious for the present proposal.