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 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 and schizophrenia and in metabolic diseases like diabetes.

The Company’s XanaHES Phase I trial exploring the safety and tolerability of Xanamem 20mg once daily in healthy elderly volunteers, showed that the drug exhibited a good safety profile with no treatment-related serious adverse events.  Additionally, the trial demonstrated that Xanamem produced a statistically significant improvement in cognition, which, along with other data recently generated, confirms the underlying mechanism of action of Xanamem.

The Company plans to initiate Phase II studies of Xanamem against various diseases as soon as possible after the current COVID19 health crisis affecting the globe; including in Alzheimer’s disease, and in cognitive impairment associated with schizophrenia and diabetes.

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.

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 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.

MECHANISM OF ACTION

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.

Xanamem was discovered by researchers at the University of Edinburgh (UoE) in Scotland and has been under development for over a decade. In late 2014, Actinogen Medical licensed the global rights to Xanamem, and a number of backup compounds, with the commitment to actively progress the clinical development of these promising compounds. Xanamem is the lead compound under development and is currently well advanced into Phase II clinical development.

ACTINOGEN’S JOURNEY TO DISCOVERY

UE2343

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.

Ownership & Financial Support

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.

Xanamem

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.

CONFIRMING XANAMEM'S EFFICACY

Phase I – XanaHES

XanaHES was a Phase I, Single Blinded, Central Reader Blinded, Placebo-Controlled, Dose Escalation Study of Xanamem™ to Assess Safety and Tolerability in Healthy Elderly Subjects.

This safety study was conducted by Linear Clinical Research, QEII Medical Centre, Western Australia.

The purpose of this study was to evaluate the safety and tolerability of Xanamem 20 mg once daily (QD) from Baseline to End of Treatment (EOT) as measured by multiple, objective items of overall safety and Nerve Function Monitoring (NFM). The trial also included an exploratory assessment of cognition, using the industry standard Cogstate Cognitive Test Battery to evaluate six domains of cognition. Additional exploratory objectives consisted of serum cortisol measurements, serum PK and optional Cerebrospinal Fluid (CSF) sample analysis.

PUBLICATIONS

Publications
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.

Publications
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 neuroscience10(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.

Publications
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.

Publications
Assessing Premorbid Cognitive Ability in Adults With Type 2 Diabetes Mellitus-a Review With Implications for Future Intervention Studies

Wong, R. H. X., Scholey, A. & Howe, P. R. C. 2014. Current Diabetes Reports, 14, 12.

Risk of dementia in diabetes mellitus: a systematic review

Biessels, G. J., Staekenborg, S., Brunner, E., Brayne, C. & Scheltens, P. 2006. Lancet Neurology, 5, 64-74.

The link between iron, metabolic syndrome, and Alzheimer’s disease

Grunblatt, E., Bartl, J. & Riederer, P. 2011. Journal of Neural Transmission, 118, 371-379.

A Meta-Analysis of Cognitive Functioning in Nondemented Adults with Type 2 Diabetes Mellitus

Monette, M. C. E., Baird, A. & Jackson, D. L. 2014. Canadian Journal of Diabetes, 38, 401-408.

Magnitude of Cognitive Dysfunction in Adults with Type 2 Diabetes: A Meta-analysis of Six Cognitive Domains and the Most Frequently Reported Neuropsychological Tests Within Domains

Palta, P., Schneider, A. L. C., Biessels, G. J., Touradji, P. & Hill-Briggs, F. 2014. Journal of the International Neuropsychological Society, 20, 278-291.

Contribution of metabolic syndrome components to cognition in older individuals

Dik, M. G., Jonker, C., Comijs, H. C., Deeg, D. J. H., Kok, A., Yaffe, K. & Penninx, B. W. 2007. Diabetes Care, 30, 2655-2660.

The global prevalence of dementia: A systematic review and meta-analysis

Prince, M., Bryce, R., Albanese, E., Wimo, A., Ribeiro, W. & Ferri, C. P. 2013. Alzheimers & Dementia, 9, 63-75.

Global Epidemiology of Dementia: Alzheimer’s and Vascular Types

Rizzi, L., Rosset, I. & Roriz-Cruz, M. 2014. Biomed Research International, 8.

Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition

Saeedi, P., Petersohn, I., Salpea, P., Malanda, B., Karuranga, S., Unwin, N., Colagiuri, S., Guariguata, L., Motala, A. A., Ogurtsova, K., Shaw, J. E., Bright, D., Williams, R., Almutairi, R., Montoya, P. A., Basit, A., Besanccon, S., Bommer, C., Borgnakke, W., Boyko, E., Chan, J. L., Divakar, H., Esteghamati, A., Forouhi, N., Franco, L., Gregg, E., Hassanein, M., Ke, C., Levitt, D., Lim, L. L., Ogle, G. D., Owens, D., Pavkov, M., Pearson-Stuttard, J., Ramachandran, A., Rathmann, W., Riaz, M., Simmons, D., Sinclair, A., Sobngwi, E., Thomas, R., Ward, H., Wild, S., Yang, X. L., Yuen, L. L., Zhang, P. & Comm, I. D. F. D. A. 2019. Diabetes Research and Clinical Practice, 157, 10.

Diabetes in Midlife and Cognitive Change Over 20 Years A Cohort Study

Rawlings, A. M., Sharrett, A. R., Schneider, A. L. C., Coresh, J., Albert, M., Couper, D., Griswold, M., Gottesman, R. F., Wagenknecht, L. E., Windham, B. G. & Selvin, E. 2014. Annals of Internal Medicine, 161, 785-U68.

Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI)

Ritchie, C., Smailagic, N., Noel-Storr, A. H., Takwoingi, Y., Flicker, L., Mason, S. E. & Mcshane, R. 2014. Cochrane Database of Systematic Reviews, 91.

Diabetes and Cognitive Impairment

Zilliox, L. A., Chadrasekaran, K., Kwan, J. Y. & Russell, J. W. 2016. Current Diabetes Reports, 16, 11.