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 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 quite normal, if cortisol remains elevated for long periods of time, it can become toxic to the neurons (nerve cells) in the brain. Patients with raised cortisol include those with diabetes, with depression, schizophrenia and PTSD, and many patients with Alzheimer’s disease. Interestingly, blood cortisol levels tend to also rise with normal ageing.

Data from several major studies have consistently shown an association between increased cortisol and cognitive decline, together 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 low cortisol levels. The study authors concluded that therapies aimed at lowering plasma cortisol levels should be considered as a way to prevent the development of Alzheimer’s disease.

Mechanism of Action

Xanamem blocks the activity of 11β-HSD1, an enzyme that converts inactive cortisone into its active form, cortisol in the brain. Blocking the activity of the enzyme therefore reduces the amount of cortisol in the brain. The enzyme is present in high concentrations in the hippocampus and the frontal cortex, the parts of the brain most associated with recent memory and behaviour, and the regions of the brain 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 acquired the global rights to Xanamem, with the commitment to actively progress the clinical development of this very promising compound.

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).

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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