XANAMEM ™

The cortisol hypothesis and Alzheimer’s disease

Xanamem has been 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 and progression of 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.

Data from several major studies have consistently shown an association between increased cortisol levels and cognitive decline, that in turn together correlate with development of 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 is currently in Phase II trial (XanADu). The future development of the drug will be shaped by the results from this trial.

Mechanism of Action

Xanamem blocks the activity of 11β-HSD1, an enzyme that converts inactive cortisone into its active form cortisol. Blocking the activity of the enzyme reduces the amount of cortisol, and as Xanamem penetrates the blood-brain barrier, it achieves reduction in cortisol directly within the brain. The enzyme is present in high concentrations in the hippocampus and the frontal cortex, which are the regions of the brain associated with recent memory and behaviour, and most affected by Alzheimer’s disease.

Xanamem was discovered by researchers at the University of Edinburgh in Scotland, and has been under development for over a decade. In late 2014, Actinogen Medical licenced the global rights to Xanamem, and a number of backups, with the commitment to actively progress the clinical development of these promising compounds. Xanamem is the lead compound under development.

ACTINOGEN’S JOURNEY TO DISCOVERY

CONFIRMING XANAMEM'S EFFICACY

In a mouse model of Alzheimer’s disease, Xanamem was effective in improving cognitive function and in clearing amyloid plaques from the brain. The improved cognitive function was observed after only 4 weeks of treatment, and was maintained for at least 41 weeks. If Xanamem can be demonstrated to be as effective in humans, it has the potential to be one of the most meaningful global medical breakthroughs for treating Alzheimer’s disease in decades.

PUBLICATIONS

Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer’s disease

Endocrinology, 1-12. Sooy, K., Noble, J., McBride, A., Binnie, M., Yau, J. L. W., Seckl, J. R., Walker, B. R., & Webster, S. P. (2015).

Selection and early clinical evaluation of the brain-penetrant 11β- hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor UE2343 (Xanamem™)

British Journal of Pharmacology. Scott P Webster, AndrewMcBride, Margaret Binnie, Karen Sooy, Jonathan R Seckl, Ruth Andrew, T David Pallin, Hazel J Hunt, Trevor R Perrior, Vincent S Ruffles, J William Ketelbey, Alan Boyd and Brian R Walker (2017).

Discovery and biological evaluation of adamantyl amide 11β-HSD1 inhibitors

Bioorganic & medicinal chemistry letters, 17(10), 2838-2843. Webster, S. P., Ward, P., Binnie, M., Craigie, E., McConnell, K. M., Sooy, K., Vinter, A., Seckl, J.R. & Walker, B. R. (2007).

Environmental novelty exacerbates stress hormones and Aβ pathology in an Alzheimer’s model

Nature Scientific Reports 7: 2764. Kimberley E. Stuart, Anna E. King, Carmen M. Fernandez-Martos, Mathew J. Summers & James C. Vickers (2018)

Circulating cortisol and cognitive and structural brain measures

Neurology: 10-1212. Echouffo-Tcheugui, Justin B., Sarah C. Conner, Jayandra J. Himali, Pauline Maillard, Charles S. DeCarli, Alexa S. Beiser, Ramachandran S. Vasan, and Sudha Seshadri (2018)

Plasma Cortisol, Brain Amyloid-β, and Cognitive Decline in Preclinical Alzheimer’s Disease: A 6-Year Prospective Cohort Study

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging. Robert H. Pietrzak, Simon M. Laws, Yen Ying Lim, Sophie J. Bender, Tenielle Porter, James Doecke, David Ames, Christopher Fowler, Colin L. Masters, Lidija Milicic, Stephanie Rainey-Smith, Victor L. Villemagne, Christopher C. Rowe, Ralph N. Martins, and Paul Maruff, for the Australian Imaging, Biomarkers and Lifestyle Research Group (2017).

Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer’s type

Neurobiology of Aging, 36, 601-607. Popp, J., Wolfsgruber, S., Heuser, I., Peters, O., Hull, M., Schroder, J., Moller, H. J., Lewczuk, P., Schneider, A., Jahn, H., Luckhaus, C., Perneczky, R., Frolich, L., Wagner, M., Maier, W., Wiltfang, J., Kornhuber, J., & Jessen, F. (2015).

Cortisol levels during human aging predict hippocampal atrophy and memory deficits

Nature Neuroscience, 1(1), 69-73. Lupien, S. J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N. P. V., Thakur, M., McEwen, B. S., Hauger, L., & Meaney, M. J. (1998).

Plasma cortisol and progression of dementia in subjects with Alzheimer-type dementia

American Journal of Psychiatry, 163, 2164-2169. Csernansky, J. G., Dong, H., Fagan, A. M., Wang, L., Xiong, C., Holtzman, D. M., & Morris, J. C. (2006).

Salivary cortisol, brain volumes, and cognition in community-dwelling elderly without dementia

Neurology, 85(11), 976-983. Geerlings, M. I., Sigurdsson, S., Eiriksdottir, G., Garcia, M. E., Harris, T. B., Gudnason, V., & Launer, L. J. (2015).

Plasma cortisol levels, brain volumes and cognition in healthy elderly men

Psychoneuroendocrinology, 30(5), 505-515. MacLullich, A. M., Deary, I. J., Starr, J. M., Ferguson, K. J., Wardlaw, J. M., & Seckl, J. R. (2005).

Effects of stress throughout the lifespan on the brain, behaviour and cognition

Nature reviews neuroscience, 10(6), 434-445. Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009).

Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease

Biological psychiatry, 46(12), 1595-1602. Starkman, M. N., Giordani, B., Gebarski, S. S., Berent, S., Schork, M. A., & Schteingart, D. E. (1999).

Translational Research in Stress Neuroendocrinology: 11β‐Hydroxysteroid Dehydrogenase 1 (11β‐HSD1), A Case Study

Neuroendocrinology of Stress, 327-350. Reynolds, R. M., & Webster, S. P. (2015).

Glucocorticoids increase amyloid beta and tau pathology in a mouse model of Alzheimer’s disease

J. Neurosci. 26: 9047–56 Green K.N., Billings L.M., Roozendaal B. et al. (2006).

Combined plasma and cerebrospinal fluid signature for the prediction of midterm progression from mild cognitive impairment to Alzheimer disease

JAMA neurology, 73(2), 203-212. Lehallier, B., Essioux, L., Gayan, J., Alexandridis, R., Nikolcheva, T., Wyss-Coray, T., & Britschgi, M. (2016).

Long-term cortisol measures predict Alzheimer disease risk

Neurology, 88(4), 371-378. Ennis, G. E., An, Y., Resnick, S. M., Ferrucci, L., O’brien, R. J., & Moffat, S. D. (2017).

Hippocampal damage associated with prolonged glucocorticoid exposure in primates

J Neurosci. 10: 2897–2902. Sapolsky RM, Uno H, Rebert CS et al. (1990).

11ß -hydroxysteroid dehydrogenase type 1 inhibitor use in human disease- a systematic review and narrative synthesis

Metabolism: Clinical and Experimental. Gregory, S., Hill, D., Grey, B., Ketelbey, W., Miller, T., Muniz-Terrera, G. and Ritchie, C.W., 2020.

Midlife stress alters memory and mood-related behaviors in old age: Role of locally activated glucocorticoids

Psychoneuroendocrinology 89 (2018) 13–22. Nicola Wheelan, Christopher J. Kenyon, Anjanette P. Harris, Carolynn Cairns, Emad Al Dujaili, Jonathan R. Seckl, Joyce L.W. Yau (2018)

11β-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics

PNAS, 101(17), 6734-6739. Sandeep, T. C., Yau, J. L. W., MacLullich, A. M. J., Noble, J., Deary, I. J., Walker, B. R., & Seckl, J. R. (2004).

Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzheimer’s disease

Endocrinology, 1-12. Sooy, K., Noble, J., McBride, A., Binnie, M., Yau, J. L. W., Seckl, J. R., Walker, B. R., & Webster, S. P. (2015).

Inhibiting 11β-hydroxysteroid dehydrogenase type 1 prevents stress effects on hippocampal synaptic plasticity and impairs contextual fear conditioning

Neuropharmacology, 81, 231-6. Sarabdjitsingh, R. A., Zhou, M., Yau, J. L., Webster, S. P., Walker, B.R., Seckl, J. R., Joëls, M., & Krugers, H. J. (2014).

11beta-hydroxysteroid dehydrogenase type 1 deficiency prevents memory deficits with aging by switching from glucocorticoid receptor to mineralocorticoid receptor-mediated cognitive control

Journal of Neuroscience, 31(11), 4188 – 4193. Yau, J. L., Noble, J., & Seckl, J. R. (2011).

11β-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline

Journal of Neurobiological Aging, 33(1), 5406-13. MacLullich, A. M. 1., Ferguson, K. J., Reid, L. M., Deary, I. J., Starr, J. M., Wardlaw, J. M., Walker, B. R., Andrew, R., & Seckl, J. R. (2012).

Acute inhibition of 11beta-hydroxysteroid dehydrogenase type-1 improves memory in rodent models of cognition

Journal of Neuroscience, 31(4), 5406-13. Mohler, E. G., Browman, K. E., Roderwald, V. A., Cronin, E. A., Markosyan, S., Scott Bitner, R., Strakhova, M. I., Drescher, K. U., Hornberger, W., Rohde, J. J., Brune, M. E., Jacobson, P. B., & Rueter, L. E. (2011).

11beta-hydroxysteroid dehydrogenase type 1 expression is increased in the aged mouse hippocampus and parietal cortex and causes memory impairments

Journal of Neuroscience, 30(20), 6916-20. Holmes, M. C., Carter, R. N., Noble, J., Chitnis, S., Dutia, A., Paterson, J. M., Mullins, J. J., Seckl, J. R., Yau, J.L. (2010).

Partial deficiency or short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice

Journal of Neuroscience, 30(41), 13867-13872. Sooy, K., Webster, S. P., Noble, J., Binnie, M., Walker, B. R., Seckl, J. R., & Yau, J. L. W. (2010).

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