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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 has demonstrated potent effects on pharmacodynamics biomarkers, consistent with substantial inhibition of 11β-HSD1 for at least 24 hours after single doses. This was assessed in terms of changes in urinary cortisol metabolites; a reduction in both the urinary tetrahydrocortisol (THF)/ tetrahydrocortisone (THE) ratio, as well as plasma adrenocorticotropic hormone (ACTH) levels. Xanamem™ also displayed oral exposure in line with twice daily dosing. More information on this completed Phase I study of Xanamem™ in healthy subjects can be found at Clinicaltrials.gov.
A Phase I, 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 our future studies, which supported a twice-daily dosing regimen.
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 adequately inhibit the excess production of cortisol in the hippocampus and frontal cortex, 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.
The results from both the Phase I studies are currently being drafted into a manuscript for publication in a prestigious, peer-reviewed, medical journal in 2016.
Actinogen Medical’s current clinical research includes plans to conduct a Phase II clinical trial in mild dementia, due to Alzheimer’s disease. This XanADu trial protocol, will include significant input from our Xanamem™ Clinical Advisory Board, and the Scientific Development Panel – the original discoverers of Xanamem™ at the University of Edinburgh – as well as the relevant regulatory bodies and ethics committees.
The trial will recruit around 174 patients across Australia, the United Kingdom, and the United States of America. Results from the trial are expected in 2018. XanADu, a double-blind placebo controlled study, aims to demonstrate the effectiveness of Xanamem™ in treating patients with mild dementia due to Alzheimer’s disease. Some of the design features are provided in the table below.
For further information and updates on XanADu, and for more information on Xanamem™ in Alzheimer’s disease, please refer to Clinicaltrials.gov (identifier: NCT02727699).
Actinogen Medical is currently conducting clinical research for other potential indications for Xanamem™ in the following areas:
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You can also track any current clinical research and project updates in our Clinical Product Pipeline section.
Actinogen Medical is open to discussing potential research partnerships in any of these areas. See our Partnership Opportunities page for more information.
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).
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).
Csernansky, J. G., Dong, H., Fagan, A. M., Wang, L., Xiong, C., Holtzman, D. M., & Morris, J. C. (2006). Plasma
cortisol and progression of dementia in subjects with Alzheimer-type dementia. American Journal of Psychiatry, 163, 2164-2169.
De Querain, et. al. (2004). Geerlings, M. I., Sigurdsson, S., Eiriksdottir, G., Garcia, M. E., Harris, T. B., Gudnason, V., & Launer, L. J. (2015). Salivary cortisol, brain volumes, and cognition in community-dwelling elderly without dementia. Neurology, 85, 1-8.
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). 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. Article Page.
Kilgour, A. H. 1., Semple, S., Marshall, I., Andrews, P., Andrew, R., & Walker, B.R. (2014). 11β-Hydroxysteroid dehydrogenase activity in brain does not contribute to systemicc interconversion of cortisol and cortisone in healthy men. Journal of Clinical Endocrinology and Metabolism, 100(2), 483-9. Article Page.
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). Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nature Neuroscience, 1(1), 69-73.
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). 11β-hydroxysteroid dehydrogenase type 1, brain atrophy and cognitive decline. Journal of Neurobiological Aging, 33(1), 5406-13. Article Page.
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). Acute inhibition of 11beta-hydroxysteroid dehydrogenase type-1 improves memory in rodent models of cognition. Journal of Neuroscience, 31(4), 5406-13. Article Page.
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). Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer’s type. Neurobiology of Aging, 36, 601-607.
Sandeep, T. C., Yau, J. L. W., MacLullich, A. M. J., Noble, J., Deary, I. J., Walker, B. R., & Seckl, J. R. (2004). 11β-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. PNAS, 101(17), 6734-6739.
Sarabdjitsingh, R. A., Zhou, M., Yau, J. L., Webster, S. P., Walker, B.R., Seckl, J. R., Joëls, M., & Krugers, H. J. (2014). Inhibiting 11β-hydroxysteroid dehydrogenase type 1 prevents stress effects on hippocampal synaptic plasticity and impairs contextual fear conditioning. Neuropharmacology, 81, 231-6. Article Page. Seckl, et. al. (2004).
Sooy, K., Noble, J., McBride, A., Binnie, M., Yau, J. L. W., Seckl, J. R., Walker, B. R., & Webster, S. P. (2015). Cognitive and disease-modifying effects of 11β-hydroxysteroid dehydrogenase type 1 inhibition in male Tg2576 mice, a model of Alzhimer’s disease. Endocrinology, 1-12.
Sooy, K., Webster, S. P., Noble, J., Binnie, M., Walker, B. R., Seckl, J. R., & Yau, J. L. W. (2010). Partial deficiency of short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 improves cognitive function in aging mice. Journal of Neuroscience, 30(41), 13867-13872.
Wagner. (2010). Moving beyond the rules: The development of a central nervous system multiparameter optimisation (CNS MPO) approach to enable alignment of druglike properties. ACS Chemistry and Neuroscience, 1(6), 435-449.
Walker, B. R., & Webster, S. P. (2014). Corticrine opinion – results for ABT-384. University of Edinburgh. Document Page.
Yau, J. L., Noble, J., & Seckl, J. R. (2012). 11beta-hydroxysteroid dehydrogenase type 1 deficiency prevents memory deficits with aging by switching from glucocorticoid receptor to mineralocorticoid receptor-mediated cognitive control. Journal of Neuroscience, 31(11), 4188-93. Article Page.
Yau, J. L., Wheelan, N., Noble, J., Walker, B. R., Webster, S. P., Kenyon, C. J., Ludwig, M., & Seckl, J. R. (2014).Intrahippocampal glucocorticoids generated by 11β-HSD1 affect memory in aged mice. Journal of Neurobiological Aging, 36(1), 334-43. Article Page.
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 exploring partners wishing to co-develop Xanamem™ for the Japanese and other Asian markets.
Actinogen aims to grow the business pipeline through partnering, licencing, and/or acquiring additional early stage candidates in CNS and metabolic diseases, which align with areas of strong commercial and technical capabilities.
Actinogen is open to receiving both private or public capital investment to support its R&D strategy.