Clinical Development Pipeline

Actinogen targeting a diverse portfolio of indications

PRE-CLINICAL

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.

TOXICOLOGY

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 diseases associated with raised cortisol.

CLINICAL

PHASE I – SINGLE ASCENDING DOSE (SAD)

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 11β-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 Clinicaltrials.gov (Identifier: NCT02616445) and in Webster et al 2017.

PHASE I – MULTIPLE ASCENDING DOSE (MAD)

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. The primary endpoint of the study demonstrated the safety, tolerability, and pharmacokinetics of Xanamem. Additionally, the trial confirmed Xanamem efficiently crosses the blood-brain barrier in concentrations that are expected to adequately inhibit the excess production of cortisol in the brain.

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

Phase II – XanADu

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, the UK and USA.

The initial results from the XanADu trial were announced in May 2019. The trial established that a 10mg daily dose of Xanamem is safe and inhibits cortisol production, as demonstrated by the expected increase in related hormones, including adrenocorticotropic hormone (ACTH), androstenedione, and DHEAS. However, Xanamem at 10mg daily did not demonstrate adequate efficacy in improving cognition in mild, clinically diagnosed Alzheimer’s disease over a 12 week period. The primary and secondary endpoint measures did not show statistical differences between Xanamem 10mg and placebo.

While it is clear that Xanamem is a pharmacologically active drug, further analysis of the XanADu dataset coupled with the output and analyses of the other ongoing Xanamem studies (summarised below), have informed the future strategic clinical development program for the drug.

Further information and updates on XanADu, can be found at Clinicaltrials.gov.

Phase I – XanaHES

XanaHES was a Phase I, single-blinded, central reader blinded, placebo-controlled study of Xanamem® to assess safety and tolerability in healthy elderly subjects, and explore cognitive activity with the Cogstate Cognitive Test Battery.

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

The safety and tolerability of Xanamem 20 mg or placebo, given once daily (QD), was studied over 12 weeks from Baseline to End of Treatment (EOT). As well as safety assessments, the trial also included an exploratory assessment of cognition, using the industry standard Cogstate Cognitive Test Battery to evaluate six domains of cognition.

Positive and clinically meaningful effects were seen in multiple domains of the Cogstate test, and these were statistically significant at EOT for attention and working memory.

PHASE I – TARGET OCCUPANCY

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 provides 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 will reveal the optimal dose where maximum binding at the enzyme receptor sites is achieved. This information is being used in parallel with the XanADu and XanaHES study data to inform the further clinical development of Xanamem.

Interim data suggest good target occupancy of doses of 5mg daily and above.

Advisory Boards

Xanamem Clinical Advisory Board

Scientific Advisory Board

Publications

Publications
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.

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 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.

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
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.

PARTNERSHIP OPPORTUNITIES

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

Modulation of cortisol levels via treatment with Xanamem is potentially clinically useful for a broad range of neurological and metabolic disorders associated with elevated cortisol.

Actinogen is seeking commercial partners to co-invest in the clinical development of Xanamem, to study its use in a variety of strategic indications in addition to those being actively pursued by the company.

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

EXTERNAL LINKS

Alzheimer's disease

Alzheimer’s Association (United States): Brain Basics
https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour
Alzheimer’s Association (United States): Disease and the Brain
https://www.alz.org/alzheimers-dementia/what-is-alzheimers/brain_tour
Alzheimer’s Research (United Kingdom): Share The Orange
https://www.alzheimersresearchuk.org/orange/
Alzheimer’s Society (United Kingdom)
http://www.alzheimers.org.uk/info/20033/publications_and_factsheets
Dementia Australia: Help Sheets
https://www.dementia.org.au/resources/help-sheets

Fragile X Syndrome

Fragile X Association of Australia
https://www.fragilex.org.au/understanding-fragile-x/

‘Stuart X’ A short film about a Fragile X sufferer
https://www.youtube.com/watch?v=uKyGX-RJFiw&feature=youtu.be

US National Fragile X Foundation
https://fragilex.org/

Schizophrenia

Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD)
https://www.neura.edu.au/sri/

SANE Australia – National mental health Charity
https://www.sane.org/information-stories/facts-and-guides/schizophrenia

Schizophrenia and Related Disorders Alliance of America (SARDAA)
https://sardaa.org/about-sardaa/

Diabetes

Australasian Diabetes Society
https://diabetessociety.com.au/

American Diabetes Association (ADA)
https://www.diabetes.org/

Diabetes Australia
https://www.diabetesaustralia.com.au/

Diabetes UK
https://www.diabetes.org.uk/

International Diabetes Federation
https://idf.org/