A Phase I, single ascending dose (SAD), randomised, double-blind, placebo-controlled study was successfully completed in 2013 with 48 healthy human volunteers. Xanamem was well tolerated with no serious adverse events, and demonstrated potent effects on pharmacodynamic biomarkers, consistent with substantial inhibition of 11B-HSD1 for at least 24 hours after a single dose.

More information on this completed Phase I study of Xanamem in healthy subjects can be found at (Identifier: NCT02616445) and in Webster et al 2017.


A second Phase I study, a multiple ascending dose (MAD), randomised, double-blind, placebo-controlled study in 40 healthy volunteers was successfully completed in 2015. Participants were given doses of 10mg, 20mg and 35mg Xanamem twice daily for nine days, and once on the morning of the tenth day (19 doses in total). The primary endpoint of the study confirmed the safety and tolerability of Xanamem. Additionally, the trial demonstrated the pharmacokinetics of Xanamem and helped define the optimal dose for future studies.

Two additional sub-studies included a fed-fasted study to confirm the effect of food on the absorption of Xanamem, and a cerebrospinal fluid (CSF) pharmacokinetic study. This key CSF sub-study confirmed Xanamem efficiently crosses the blood-brain barrier in concentrations that adequately inhibit the excess production of cortisol in the brain.

This Multiple Ascending Dose (MAD) study was conducted by Linear Clinical Research, a world-class clinical trial facility that is part of the QEII Medical Centre in Perth, Australia.

More information on this completed Phase I Study of Xanamem in healthy subjects can be found at (Identifier: NCT02616445) and Webster et al 2017.


In 2016, Actinogen Medical initiated XanADu, a Phase II, double-blind, 12-week, randomised, placebo-controlled study to assess the safety, tolerability and efficacy of 10mg daily Xanamem in patients with mild Alzheimer’s disease. Patient recruitment and treatment commenced in mid-2017 and was completed in 2018 with 186 patients randomised across 25 sites in Australia, UK and USA. Results were announced in Q2 CY19. Some of the design features are provided in the table below.

Further information and updates on XanADu, can be found at

About XanADu’s Clinical Endpoints

Actinogen’s XanADu trial has seven clinical efficacy endpoints, which are all accepted and endorsed by regulators (such as the FDA) and academia as standard endpoints for use in Alzheimer’s R&D. Each endpoint consists of multiple domains resulting in numerous potential combinations of results and outcomes.

Importantly, the outcome of the trial is not dependent on one single endpoint, as the future development of Xanamem will be defined by the totality of these endpoint results – results from XanADu and from the additional Xanamem studies initiated since mid-2018. These results will all assist in informing the optimum way forward for the further development of Xanamem.


ADAS-COG14 (AD Assessment Scale Cognition v14)

ADAS-COG14 is one of the most frequently used tests, primarily focusing on the domains of language and memory.

The assessment evaluates: word recall (including delayed word recall), understanding and following commands, constructional and ideational praxis, naming objects, orientation, word recognition, remembering instruction, comprehension of spoken language, word finding difficulty, spoken language ability and executive function.

ADCOMS (AD Composite Score)

ADCOMS is a composite of selected domains of ADAS-COG, CDR-SOB and MMSE, that are considered most sensitive to detect change in mild Alzheimer’s disease.

ADCOMS is a breakthrough cognition measurement instrument and is considered the most sensitive currently available. It is being increasingly adopted in Alzheimer’s trials and is expected to become a routine endpoint for clinical trials investigating new drugs designed to treat mild Alzheimer’s.


CDR-SOB (Clinical Dementia Rating Sum of Boxes)

CDR-SOB assesses multiple cognitive and functional domains through interviews with the patient and caregiver. It assesses memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care.

RAVLT (Rey Auditory Verbal Learning Test)

RAVLT assesses the cognitive domains of verbal learning and memory through interviewing the patient. It involves a series of word list recall tests.

MMSE (Mini-Mental State Examination)

MMSE assesses cognitive impairment and is directed at the patient. It assesses memory and particularly recent memory, orientation in time and place, recognition, attention and calculation, concentration, language and praxis.

NPI (Neuropsychiatric Inventory)

NPI is an assessment conducted with the caregiver to obtain information on the psychopathology of the patient. This scale assesses whether the patient is experiencing problems with delusions or hallucinations, agitation, depression, anxiety, disinhibition, irritability, apathy, sleep or nighttime behaviour disorders, appetite and eating disorders.

NTB (Neuropsychological Test Battery)

NTB assesses the domains of working memory and executive function. The assessment includes questions on memory, attention, processing speed, visuo-spatial function, praxis, language and abstraction.


XanaHES is 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 is currently being conducted by Linear Clinical Research, QEII Medical Centre, Western Australia.

The purpose of this study is to evaluate the safety and tolerability of Xanamem 20mg and 30mg once daily (QD) from baseline to end of treatment (EOT) as measured by multiple, objective items of overall safety and Nerve Function Monitoring (NFM). Additional exploratory objectives consist of CogState electronic cognitive measurements, cortisol measurements, serum PK and optional Cerebrospinal Fluid (CSF) samples.

The study commenced in Q1 2019 and top-line results of the first Cohort (20mg) are expected in Q2 2019.


This is a positron emission tomography (PET) trial assessing receptor occupancy of multiple doses of Xanamem using the 11β-HSD1-specific radiolabelled imaging tracer 11C-TARACT002.

Use of [11C]TARACT002 will provide the opportunity for Actinogen to demonstrate that Xanamem binds to the 11β-HSD1 enzyme in the brain through a competitive binding PET study. Quantification of the binding and uptake curves of Xanamem across four different dose levels (10 mg, 20 mg, 30 mg, 40 mg) will reveal the optimal dose where maximum uptake at the enzyme receptor sites is achieved. This information will be used in parallel with the XanADu and XanaHES studies to inform the further development of Xanamem.


Actinogen has conducted a substantial number of pre-clinical studies with Xanamem, covering all mandated pre-clinical investigations across aspects of absorption, distribution, metabolism, and excretion (ADME), as well as acute toxicology, genotoxicity, immunotoxicity, photo safety testing, and drug-drug interaction studies. Planned pre-clinical studies include carcinogenicity, developmental and reproductive toxicology (DART), and additional drug-drug interaction studies.

The pre-clinical studies currently being conducted by Actinogen are listed below:


Multiple pre-clinical studies are currently being conducted to further support the generation of a brain-penetrant PET Ligand with Xanamem for the upcoming Phase 1 Target Occupancy Study:

  • Lead Profile Screening with PET Ligand
  • Genotoxicity Study of PET Ligand with AMES
  • Single Dose Acute Safety Study in Rats with PET Ligand
  • Hepatic Microsome Studies with PET Ligand
  • Homogenate Binding Studies in Human & AD Brain Tissue with Autoradiography with Xanamem and PET Ligand



Actinogen is conducting a range of toxicology studies as required by the regulatory authorities in the development of any drug, and particularly with drugs that are likely to be used long-term, like Xanamem. These studies will help define and guide the safe long-term use of Xanamem in humans, as will be necessary in the potential treatment of Alzheimer’s disease, and other neurological and metabolic diseases associated with raised cortisol.




Cognitive impairment within mood disorders (unipolar depression, bipolar disorder), as well as schizophrenia, has been studied extensively. Importantly patients with the mood disorders and schizophrenia commonly have associated persistently raised cortisol. In general, unipolar and bipolar patients show impaired performance in cognitive tests of attention, executive function, and memory, and cognitive impairment can be one of the more debilitating consequences of schizophrenia. Increased cognitive dysfunction often is associated with greater symptom severity and patients who present for the first time to a practitioner with complaints of mood disorders are at greater risk of going on to develop Alzheimer’s disease (AD).

Evidence that cognitive decline might develop in conjunction with mood disorders has been confirmed through multiple research studies. A 7-year study followed more than 600 healthy elderly (greater than 64 years old) on measures of mood and cognition. Participants with no depressive symptoms at study intake presented mild, yet progressive, cognitive decline annually, presumably due to the natural effects of aging. With each additional depressive symptom presented at intake, however, the annual rate of cognitive decline increased by 24%. Thus, the number of depressive symptoms at baseline was associated with increased risk of developing AD.

Research has shown a relationship between mood, cognitive decline, and neurological dysfunction. Few studies have, however, examined all three symptom domains within one investigation, and none have used a cortisol inhibitor like Xanamem to test the hypothesis underlying the mechanisms controlling the development and progression of cognitive decline in mood disorders.

Actinogen is currently evaluating the potential to study Xanamem in the treatment of cognitive impairment associated with mood disorders and schizophrenia.


Actinogen Medical is open to receiving expressions of interest from academic and commercial parties looking to develop research partnerships in Actinogen’s focus areas.

In particular, Actinogen is seeking commercial partners to co-invest in the clinical development of Xanamem in secondary indications.

Actinogen is open to receiving both private or public capital investment to support its R&D strategy.


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 neuroscience10(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).

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).