MICA: Assessing the therapeutic efficacy of 11beta-hydroxysteroid dehydrogenase type 1 inhibitor (AZD4017) in idiopathic intracranial hypertension

Idiopathic intracranial hypertension (IIH), a condition of raised brain pressure, is a common cause of blindness in young overweight women. The underlying cause of the condition has not been fully established and the best way to treat IIH is not known. Drugs such as acetazolamide, have not been shown to be effective and additionally have intolerable side effects. Brain fluid shunting surgery can be used to save vision, but shunts block in over half of patients and therefore need replacing, often multiple times. Treatments such as weight loss are notoriously difficult. Our recent research has highlighted the potential role of an enzyme that generates steroid locally in brain tissues. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) generates active steroid within the parts of the brain that produce cerebrospinal fluid (CSF) - the fluid that bathes the brain. Production of too much CSF can lead to increased brain pressure in IIH and we believe that 11beta-HSD1 drives this process in IIH. Additionally, we have demonstrated that weight loss and brain pressure reduction which significantly improve IIH also reduced 11beta-HSD1 activity. We therefore suggest that reducing 11beta-HSD1, with an oral tablet of AZD4017 (an inhibitor of 11beta-HSD1 developed by AstraZeneca) may represent a landmark treatment for IIH.
Through a partnership between AstraZeneca and University of Birmingham we will conduct a randomised, blinded, clinical study (24 patients) to look at the effectiveness, safety and side effects of AZD4017 in the treatment of IIH. Patients will undergo a series of investigations to assess brain pressure (through a lumbar puncture), vision and headaches at the start and end of the 3 month study. We will also be conducting regular monitoring of urine and blood alongside detailed patient assessments to evaluate drug safety and side effects.
This will be the first study to investigate the role of 11beta-HSD1 inhibitors in IIH and has the potential to offer a novel treatment in this condition which can cause blindness. Additionally, if effective, AZD4017 may have uses in other neurological conditions where the morbidity is related to elevated brain pressure.

Idiopathic intracranial hypertension (IIH), is a common condition of unknown aetiology affecting the young obese female population (20 per 100,000). Faced with the global obesity epidemic, its incidence is expected to rise further. IIH is characterised by elevated intracranial pressure (ICP) which manifests as disabling headaches and severe visual loss in up to 25% of patients. An evidence base for treatment has not been established and there are currently no effective and tolerable pharamcotherapeutic options. Based upon our in-vitro observations, we have hypothesised that increased local glucocorticoid generation through the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) within the choroid plexus that generates cerebrospinal fluid (excess production leading to raised ICP) is crucial to the pathogenesis of IIH. This mechanism is analogous to that occurring in the ocular ciliary body which produces aqueous humor where 11beta-HSD1 inhibitors have been shown to lower intraocular pressure. We have recently published a seminal study in patients with IIH and demonstrated that weight loss significantly reduced 11beta-HSD1 activity, ICP and dramatically improved patient symptoms; the observed reduction in ICP correlated directly with the reduction in ICP.

In collaboration with our industrial partner, AstraZeneca (AZ), we will conduct a double blind, placebo controlled randomised phase II study to assess the tolerability, safety and efficacy of the selective 11beta-HSD1 inhibitor, AZD4017, in the treatment of IIH. The study will be conducted at University Hospitals Birmingham NHS Foundation Trust, the Midlands Eye Centre and the Wellcome Trust Clinical Research Facility. In total, 24 patients with active chronic IIH (raised ICP and papilloedema) will be randomised to AZD4017 or placebo tablets (1:1).The primary outcome measure, intracranial pressure, will be evaluated by lumbar puncture at 12 weeks compared to baseline.

Over the last 2 decades, the investigators on this proposal have established glucocorticoid regeneration through the activity of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) as a therapeutic target in many conditions including idiopathic intracranial hypertension (IIH). They have published many of the seminal studies in the highest impact journals (Lancet, JCI, BMJ, Nature Genetics). Reflecting the impact of their work, in 2011, 11beta-HSD1 ranked as the 2nd most popular pharmaceutical drug target in terms of number of patents filed (>40 US patents, >90 EU patents). They have now established a unique academic-industrial collaboration between University of Birmingham and AstraZeneca (AZ) to trial the selective 11beta-HSD1 inhibitor, AZD4017 in a defined population of patients with IIH. Within this collaboration, AZ have provided the active compound and placebo as well as all relevant preclinical and phase I clinical data to facilitate study design based upon the academic hypothesis. Complementing this, UoB have brought clinical trial expertise and state-of-the-art methodologies combining neurology, ophthalmology and endocrinology. The close working relationship between University Hospital Birmingham NHS trust and the Birmingham and Midlands Eye Centre which together provide one of the largest IIH services in the country will ensure that sufficient patients are recruited through the dedicated neuro-ophthalmology clinics.
On a global level, the impact of this successful collaboration between UoB and AZ will serve as a model for other academic institutions and pharmaceutical company interactions and it is hoped that this will be adopted nationally and internationally. There are clear additional benefits of these collaborations for patients and non-academics. Patients will have the potential access to new and emerging treatments sooner than would otherwise have been possible. Furthermore, it provides the opportunity to consider indications for drug therapy that may not have been considered by the pharmaceutical company.
The specific academic impact is clear and this proposal will add significantly to the field representing the first clinical trial of this class of drug in patients with IIH. Positive results from this study targeting glucocorticoid metabolism will undoubtedly pave the way for future drug development. The impact upon patient care has the potential to be equally impressive offering a new treatment in a condition where currently proven efficacious pharmacotherapies are lacking.
In conclusion, this proposal is one of the crucial chapters in the '11beta-HSD1 story' that has developed from target identification and validation through to drug development and now to trials in disease populations. It is this final component that adds the greatest impact both academically, but perhaps more importantly to patients with the aim of improving health care.