Xanamem®

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 inside brain cells. There is a strong association between cortisol and structural 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 1 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 2 studies evaluating Xanamem in 5mg and 10mg daily doses in the treatment of cognitive impairment associated with Alzheimer’s Disease, Major Depressive Disorder, Fragile X Syndrome and other neurological 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.

 

To see our Xanamem clinical development pipeline click here

 

The Cortisol Hypothesis

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 in 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 aging, 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 cortisol levels should be considered as a potential way of preventing the development of Alzheimer’s Disease.

Mechanism of Action

Xanamem is designed to cross the blood-brain-barrier in adequate amounts to target and block the 11β-HSD1 enzyme in the brain, and thus reduce the production of cortisol (the “stress hormone”) in neurons (brain cells). 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. Excessive cortisol is toxic to brain cells and associated with disease progression in Alzheimer’s Disease.

Publications


Xanamem clinical trials


11β-HSD1 enzyme and cognition


Cortisol and Alzheimer’s/MCI


Cortisol and Fragile X


Cortisol and Depression


Cortisol and Other Diseases

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

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

 

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

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. British Journal of Pharmacology.

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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. Journal of Neurobiological Aging, 33(1), 5406-13.

 

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

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. Journal of Neuroscience, 31(4), 5406-13.

 

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

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. Journal of Neuroscience, 30(20), 6916-20.

 

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

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

 

Circulating cortisol and cognitive and structural brain measures

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. Neurology: 10-1212.

 

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

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. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

 

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

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. Neurobiology of Aging, 36, 601-607.

 

Cortisol levels during human aging predict hippocampal atrophy and memory deficits

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. Nature Neuroscience, 1(1), 69-73.

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

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

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

 

Long-term cortisol measures predict Alzheimer Disease risk

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

 

Hippocampal damage associated with prolonged glucocorticoid exposure in primates

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

 

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

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

 

Intellectual functioning and behavioural features associated with mosaicism in Fragile X Syndrome

Baker, E. K., Arpone, M., Vera, S. A., Bretherton, L., Ure, A., Kraan, C. M., Bui, M., Ling, L., Francis, D., Hunter, M. F., Elliott, J., Rogers, C., Field, M. J., Cohen, J., Santa Maria, L., Faundes, V., Curotto, B., Morales, P., Trigo, C., Salas, I., Alliende, A. M., Amor, D. J. & Godler, D. E. 2019. Journal of Neurodevelopmental Disorders, 11, 15.

 

Biobehavioral composite of social aspects of anxiety in young adults with Fragile X Syndrome contrasted to autism spectrum disorder

Roberts, J. E., Ezell, J. E., Fairchild, A. J., Klusek, J., Thurman, A. J., Mcduffie, A. & Abbeduto, L. 2018. American Journal of Medical Genetics Part B-Neuropsychiatric Genetics, 177, 665-675.

 

Cortisol profiles differentiated in adolescents and young adult males with Fragile X Syndrome versus autism spectrum disorder

Matherly, S. M., Klusek, J., Thurman, A. J., Mcduffie, A., Abbeduto, L. & Roberts, J. E. 2018. Developmental Psychobiology, 60, 78-89.

 

Fragile X Syndrome

Hagerman, R. J., Berry-Kravis, E., Hazlett, H. C., Bailey, D. B., Moine, H., Kooy, R. F., Tassone, F., Gantois, I., Sonenberg, N., Mandel, J. L. & Hagerman, P. J. 2017. Nature Reviews Disease Primers, 3, 19.

 

HPA axis function predicts development of working memory in boys with FXS

Scherr, J. F., Hahn, L. J., Hooper, S. R., Hatton, D. & Roberts, J. E. 2016. Brain and Cognition, 102, 80-90.

 

Cortisol and behavior in Fragile X Syndrome

Hessl, D., Glaser, B., Dyer-Friedman, J., Blasey, C., Hastie, T., Gunnar, M. & Reiss, A. L. 2002. Psychoneuroendocrinology, 27, 855-872.

 

Cortisol and social stressors in children with Fragile X: A pilot study

Wisbeck, J. M., Huffman, L. C., Freund, L., Gunnar, M. R., Davis, E. P. & Reiss, A. L. 2000. Journal of Developmental and Behavioral Pediatrics, 21, 278-282.

 

Effect of glucocorticoid and 11β-hydroxysteroid-dehydrogenase type 1 (11β-HSD1) in neurological and psychiatric disorders

Dodd S, Skvarc D R, Dean OM, Anderson A, Kotowicz M, Berk M 10 Feb 2022. Int J Neuropsychopharmacol. doi: 10.1093/ijnp/pyac014.

 

Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study

J. Conradi, J. Ormel and P. de Jonge 2011. Psychological Medicine, 41, 1165–1174.

 

Depression and Hypothalamic-Pituitary-Adrenal Activation: A Quantitative Summary of Four Decades of Research

Cinnamon Stetler, PhD, And Gregory E. Miller, PhD 2011. Psychosomatic Medicine 73:114–126.

 

Central CRH system in depression and anxiety — Evidence from clinical studies with CRH1 receptor antagonists

Florian Holsboer, Marcus Ising 2008. European Journal of Pharmacology 583, 350–357.

 

Global economic burden of schizophrenia: a systematic review

Chong, Huey Yi et al. Neuropsychiatric disease and treatment vol. 12 357-73. 16 Feb. 2016, doi:10.2147/NDT.S96649

 

Spotlight on brexpiprazole and its potential in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depression

Bruijnzeel, D, and R Tandon. 2016. Drug Design, Development and Therapy 10: 1641-1647.

 

Cognitive and Disease-Modifying Effects of 11-beta Hydroxysteroid Dehydrogenase Type 1 Inhibition in Male Tg2576 Mice, a Model of Alzheimer’s Disease

Sooy, Karen. 2015. Endocrinology 156 (12): 4592-4603.

 

Efficacy of different types of cognitive enhancers for patients with schizophrenia: a meta-analysis

Sinkeviciute, I et al. 2018. NPJ Schizophrenia 4: 22.

 

Anti-dementia Drugs for Psychopathology and Cognitive Impairment in Schizophrenia: A Systematic Review and Meta-analysis

Kishi, T, and et al. 2018. International Journal of Neuropsychopharmacology 21 (8): 748-757.

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