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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Matherly, S. M., Klusek, J., Thurman, A. J., Mcduffie, A., Abbeduto, L. & Roberts, J. E. 2018. Developmental Psychobiology, 60, 78-89.
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.
Dodd S, Skvarc D R, Dean OM, Anderson A, Kotowicz M, Berk M 10 Feb 2022. Int J Neuropsychopharmacol. doi: 10.1093/ijnp/pyac014.
J. Conradi, J. Ormel and P. de Jonge 2011. Psychological Medicine, 41, 1165–1174.
Cinnamon Stetler, PhD, And Gregory E. Miller, PhD 2011. Psychosomatic Medicine 73:114–126.
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
Bruijnzeel, D, and R Tandon. 2016. Drug Design, Development and Therapy 10: 1641-1647.
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.