FROM THE LAB TO THE CLINIC:
EARLY PHASE CLINICAL RESEARCH IN HUMANS

Phase 1 – 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 pharmacodynamics 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 Clinicaltrials.gov (Identifier: NCT02616445) and in Webster et al 2017.

Phase 1 – 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. 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 how the body absorbs and metabolises Xanamem and helped define the optimal dose for the drug 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 CNS pharmacokinetic study. This key CNS sub-study confirmed Xanamem efficiently crosses the blood-brain barrier in concentrations that would adequately inhibit the excess production of cortisol in the hippocampus and frontal cortex of the brain, Xanamem’s primary site of action.

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 Clinicaltrials.gov (Identifier: NCT02616445) and Webster et al 2017.

XANADU

With the initiation of XanADu, we are now in the important next stage of Xanamem’s development. XanADu is a Phase-II trial to prove the effectiveness of Xanamem in patients with Alzheimer’s disease.

All the required studies to confirm that Xanamem is well tolerated with an acceptable safety profile to proceed into Phase II have been conducted. The studies also confirmed that Xanamem crosses the blood-brain-barrier in concentrations to adequately inhibit production of cortisol in the hippocampus and frontal cortex of the brain, its primary site of action.

Phase II Trial

In 2016, Actinogen Medical initiated XanADu, a Phase II efficacy and safety trial of Xanamem in patients with mild Alzheimer’s disease. XanADu is a double-blind, randomised, placebo-controlled study of 174 patients conducted at 20 sites across Australia, UK and USA. Patient recruitment and treatment commenced in 2017 with top-line results expected in early 2019. Some of the design features are provided in the table below.

Further information and updates on XanADu, can be found at Clinicaltrials.gov (identifier: NCT02727699).

Other indications for Xanamem

DIABETES – COGNITIVE IMPAIRMENT

For many years, raised cortisol has been recognised as a feature of diabetes, and Type 2 diabetes in particular. Unfortunately, drugs developed to reduce cortisol levels as a treatment for diabetes have not been successful, showing little clinical benefit. A small pilot study demonstrated a potential cognitive benefit in diabetics through inhibiting excess cortisol production. Individuals with Type 2 diabetes have twice the risk of developing dementia than the general population. Our collaborators at the University of Edinburgh are interested in exploring these observations further. Discussions between Actinogen Medical and the University of Edinburgh for a Phase II trial of Xanamem in Diabetes Cognitive Impairment, partially supported by Actinogen, are ongoing.

Type 2 Diabetes is a chronic disease that affects over 422 million people globally. Current treatments control blood glucose levels but have no effect on preventing dementia. If effective, Xanamem could have an enormous impact on the global burden of this disease.

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.

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.

PUBLICATIONS

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

Scientific Reports 7: 2764, DOI:10.1038/s41598-017-03016-0. Kimberley E. Stuart, Anna E. King, Carmen M. Fernandez-Martos, Mathew J. Summers & James C. Vickers (2017)

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).

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).