Xanamem’s novel mechanism of action sets it apart from other therapies for Alzheimer’s disease. It works by blocking the excess production of intracellular cortisol – the stress hormone – through the inhibition of the 11β-HSD1 enzyme in the brain. There is a strong association between persistent stress and the production of excess cortisol that leads to changes in the brain, affecting memory. The 11β-HSD1 enzyme is highly concentrated in the hippocampus and frontal cortex, the areas of the brain associated with cognitive impairment in neurological diseases, including Alzheimer’s disease.
In the Company’s recent XanaHES Phase I trial, Xanamem exhibited a statistically significant improvement in cognition among healthy older volunteers treated with 20mg Xanamem daily, and recent human target engagement data for the drug in the brain suggests good activity of doses as low as 5mg daily. The Company plans to initiate a range of Phase II studies evaluating Xanamem in the treatment of cognitive impairment associated with Alzheimer’s disease, Fragile X syndrome, and other indication(s) with a strong scientific rationale.
Xanamem is an investigational product and is not approved for use outside of a clinical trial by the FDA or by any global regulatory authority.
Xanamem was developed in response to evidence that there is a strong association between chronically raised cortisol levels in the blood and in the brain, and the development of cognitive impairment associated with a number of conditions, and Alzheimer’s disease.
Cortisol is more commonly known as the “stress hormone” and is produced in times of physical and mental stress. While this response is normal, if cortisol levels remain elevated for long periods of time, it can become toxic to the neurons (nerve cells) in the brain. Individuals with raised cortisol include those with diabetes, with depression, schizophrenia, bipolar disorder, PTSD, and many patients with Alzheimer’s disease. Interestingly, blood cortisol levels are known to rise naturally with normal ageing, with 50% of those over 65 years old having a persistently raised cortisol.
Data from several major studies have consistently shown an association between increased cortisol levels and the cognitive decline associated with a number of neurological, psychiatric and metabolic diseases. Additionally persistently raised cortisol is associated with the development of the abnormal β-amyloid protein plaques and neurotoxicity in the brain – the hallmarks of Alzheimer’s disease.
Some of the most compelling evidence supporting the cortisol hypothesis was provided by the Australian Imaging, Biomarker & Lifestyle Study of Ageing (AIBL) study published in early 2017. This study, funded by the CSIRO and several universities and medical research institutes demonstrated that healthy, elderly individuals with high cortisol levels were significantly more likely to develop Alzheimer’s disease than those with lower cortisol levels. The study authors concluded that therapies aimed at lowering blood cortisol levels should be considered as a potential way of preventing the development of Alzheimer’s disease.
Xanamem was specifically designed to block the activity of 11β-HSD1, an enzyme that converts inactive cortisone into its active form, cortisol. Additionally, Xanamem was specifically designed to cross the blood-brain-barrier, to block the 11β-HSD1 enzyme in the brain, and to reduce the production of cortisol (the “stress hormone”) in the brain. The enzyme is present in high concentrations in the hippocampus, frontal cortex and the cerebellum, the regions of the brain associated with recent memory and behaviour, and most affected by Alzheimer’s disease.
Following a decade of pioneering research into the biology of the enzyme 11β-HSD1, in 2003, the UoE researchers Prof Brian Walker, Prof Jonathan Seckl and Prof Scott Webster embarked on a drug discovery campaign to develop novel, small molecule therapeutics for the treatment of Alzheimer’s disease. The work was supported by serial Wellcome Trust technology transfer awards including a Strategic Translation Award in 2006 (£1.9M), which enabled hit-to-lead progression, and a Seeding Drug Discovery Initiative award in 2008 (£4.9M) that supported lead optimisation through to Phase 1 clinical development. Several series of inhibitors with distinct chemotypes were discovered and preclinical proof of concept in rodent studies of cognitive impairment and Alzheimer’s disease was achieved with the discovery of tool compounds UE1961 and UE2316. These studies were later published in 2010 and 2015 respectively.
The discovery in 2009 that certain compounds containing a pyrazole moiety displayed potent inhibition of 11β-HSD1 led to the synthesis of UE2343. Subsequent biological profiling of selected lead compounds was carried out and UE2343 was identified as a development candidate in late-2010. Route of synthesis development, toxicology and safety pharmacology studies were completed in mid-2012 and a clinical trials authorisation obtained in late-2012. UE2343 completed Phase I single ascending dose studies in healthy volunteers in 2013.
The University Court of the University of Edinburgh is a charitable body registered in Scotland under registration number SC005336, incorporated under the Universities (Scotland) Acts and having its main administrative offices at Old College, South Bridge Edinburgh, EHS 9YL, Scotland, United Kingdom. The University was the sole and legal owner of certain patent rights and confidential and trade secret information relating to therapeutics for dementia, related neurological disorders and metabolic disease (i.e. UE2343). In 2014, Corticrine Limited obtained from the University an exclusive right and licence under such patent rights and confidential know-how for the development and commercialization of therapeutic agents for the treatment of dementia, related neurological disorders and metabolic disease.
UE2343 was subsequently in-licenced to Actinogen Medical following the acquisition of Corticrine Limited in late 2014. UE2343 is the research code initially assigned to Xanamem by UoE; however, Xanamem may also be used to reference studies conducted with the structural analogue UE2316. For details on the extensive Xanamem development program following Actinogen’s in-licensing of Xanamem, please refer to the other R&D sections of this website.