Understanding Alzheimer's Dr. Bill Ketelbey CEO & Managing - PowerPoint PPT Presentation

Understanding Alzheimer's Dr. Bill Ketelbey CEO & Managing Director

Alzheimer’s disease is emerging as the most significant health challenge of our time 47m 75m 132m One person Total cost rise 30% of 85 year olds every 3 seconds to US$2 trillion have Alzheimer’s Disease Numbers will by 2030 double every Globally there 1 in 3 seniors will die 20 years were ~10m new cases of with Alzheimer’s Dementia will dementia in 2015 disease or other become a trillion dementia dollar disease by 2018 The Alzheimer’s Association Facts and Figures, 2014. The World Alzheimer’s Report. 2

Meet Mary • Late 80’s • Early Alzheimer's disease, otherwise generally quite well • On Aricept for the past 6 months which provided reasonable symptomatic benefit • Responded quite well initially, but the response has plateaued and has now begun to decline • No clear alternate or additional medication available 3

Alzheimer’s Drug -Development Pipeline: 2016 Source: clinicaltrials.gov as at Jan 4 th , 2016 93 agents • 74% biopharma sponsored • 50% amyloid targeted 60 50 40 30 20 10 0 Trial Data Phase I Phase II Phase III Source: Cummings, J., Morstorf, T., & Lee, G. (2016) 4

Research Drug to Medicines $ Academia Government grants Philanthropy Biotech companies Pharmaceutical companies 5

The Long Road to a New Medicine Source: www.google.com.au 6

Drug Discovery – 15 years, $1.5bn, <0.01% success! Source: Pharmaceutical Research and Manufacturers of America 7

Actinogen’s journey of discovery Xanamem™ Xanamem™ crosses blood data publication brain barrier 11 ẞ -HSD1 is highly Carbenoxolone is shown and presentation First First expressed in regions to enhance cognitive at major patent human important for cognition function in elderly men filed congresses study and type II diabetics (Sandeep et al., 2004) 11 ẞ -HSD1 11 ẞ -HSD1 knockout enzyme Xanamem™ ACW acquires mice are protected XanADu discovered development rights to Webster et al. develop against age-related starts commences selective 11 ẞ -HSD Xanamem™ cognitive dysfunction inhibitors that cross the blood brain barrier Candidate Phase II Pre-clinical Phase I optimisation XanADu wellcome trust funded Actinogen investor funded 1970 1990 2001 2004 2007 2009 2011 2013 2014 2016 2017 8

Xanamem ™: Targeting elevated cortisol at the site of action 9

Recent publications confirm association between cortisol and Alzheimer’s Plasma cortisol, brain amyloid- β , and cognitive decline in preclinical Alzheimer's disease: A 6-year prospective cohort study. Pietrzak et al . 2016 for the AIBL Research Group, Australia, US Dept. of Veterans Affairs and Yale Medical School. Accepted for publication Conclusion: “…therapies targeted toward lowering plasma cortisol…may be helpful in mitigating cognitive decline in the preclinical phase of AD.” 10

Plasma cortisol, amyloid- β, and cognitive decline in preclinical Alzheimer's disease: A 6-year prospective cohort study Robert H Pietrzak 1,2 , Simon M Laws 3,4 , Yen Ying Lim 5 , Sophie J Bender 6 , Tenielle Porter 3,4 , James Doecke 7 , David Ames 8,9 , Christopher Fowler 5 , Colin L Masters 5 , Lidija Milicic 4 , Stephanie Rainey-Smith 4 , Victor L Villemagne 5,10,11 , Christopher C Rowe 10,11 , Ralph N Martins 4,12 , & Paul Maruff 5,13 for the AIBL Research Group 1. United States Department of Veterans Affairs National Centre for Posttraumatic Stress Disorder, Clinical Neurosciences Division, VA Connecticut Healthcare System, CT, USA 2. Department of Psychiatry, Yale University School of Medicine, CT, USA 3. Ce ntre of Excellence for Alzheimer’s Disease Research and Care, Edith Cowan University, WA, Australia 4. Co -operative Research Centre for Mental Health 5. The Florey Institute, The University of Melbourne, VIC, Australia 6. School of Health Sciences, University of Notr e Dame Australia, WA, Australia 7. CSIRO, ACT, Australia 8. Academic Unit for Psychiatry of Old Age, St Vincent’s Health, The University of Melbourne, VIC, Australia 9. National Ageing Research Institute, VIC, Australia 10. Department of Nuclear Medicine and Centre for PET, Austin Health, VIC, Australia 11. Department of Medicine, Austin Health, The University of Melbourne, VIC, Australia 12. Sir James McCusker Alzheimer’s Disease Research Unit, Hollywood Private Hospital, WA, Australia 13. Cogstate Ltd., VIC Australia  Introduction  Results  Table 1: Demographic & clinical characteristics High plasma cortisol levels at baseline were associated with 2.2 Hypothalamic-pituitary-adrenal (HPA) axis dysregulation, Aβ - low Aβ - high Aβ+ low Aβ+ high p times the risk of Αβ+. Furthermore, high levels of cortisol were cortisol cortisol cortisol cortisol which is typically assessed by measuring cortisol levels, is N 158 162 50 46 associated with cognitive dysfunction, hippocampal atrophy, associated with greater decline in global cognition generally and Age 69.3 (6.6) 67.9 (6.4) 68.5 (5.5) 73.3 (7.9) < .001 were also found to increase the effect of Αβ+ on decline in global and increased risk for mild cognitive impairment and N (%) Female 86 (54.4%) 92 (56.8%) 24 (48.0%) 28 (60.9%) .60 cognition, episodic memory, and attention. Specifically, Alzheimer disease (AD). However, little is known about the N (%) APOE Ɛ4 38 (24.1%) 26 (16.0%) 26 (52.0%) 25 (54.3%) < .001 compared to Αβ+ older adults with low cortisol, Αβ+ older adults role of HPA axis dysregulation in predicting cognitive decline or in moderating the effect of high levels of amyloid- β (Αβ+) Premorbid IQ 107.9 (7.6) 108.5 (6.5) 110.5 (6.6) 109.4 (7.6) .12 with high cortisol had significantly faster decline on these measures, with Cohen’s d values of 0.69 for episodic memory, MAC-Q 25.2 (4.3) 25.2 (4.5) 25.5 (5.4) 26.3 (4.8) .63 on cognitive decline in the preclinical phase of AD, which is 0.42 for global cognition, and 0.31 for attention. These effects often protracted, and thus offers opportunities for prevention HADS 2.6 (2.2) 2.6 (2.2) 2.8 (2.9) 2.6 (2.5) .97 depression were independent of age, education, premorbid intelligence, and early intervention. We aimed to evaluate the independent HADS anxiety 4.3 (2.8) 4.3 (2.9) 4.2 (3.0) 4.5 (2.8) .93 and interactive effect of plasma cortisol levels and Αβ status APOE and BDNF genotype, subjective memory complaints, Plasma cortisol 99.2 (25.4) 191.4 (54.2) 91.0 (31.3) 187.8 (47.4) < .001 in predicting cognitive changes in the preclinical phase of AD. vascular risk factors, and depression and anxiety symptoms.  Methods  Figure 1: Group mean differences at 18-months, after accounting for baseline, for each outcome measure Cognitively normal older adults (n=416) enrolled in the AIBL study underwent Aβ neuroimaging at a single timepoint. 0.3 0.3 Fasted blood samples were collected at baseline and 0.2 0.2 analysed using a commercial cortisol ELISA, performed 0.1 0.1 Standardized Score Standardized Score according to manufacturer instructions. Because the 0 0 distribution of raw cortisol values was highly skewed and non- Low Cortisol, Low A β Low Cortisol, Low A β -0.1 -0.1 normal, and could not be corrected to normal using log 10 High Cortisol, Low A β High Cortisol, Low A β -0.2 -0.2 transformation, they were dichotomized using a median split Low Cortisol, High A β Low Cortisol, High A β -0.3 -0.3 High Cortisol, High A β High Cortisol, High A β procedure. -0.4 -0.4 -0.5 -0.5 Five cognitive composites were derived: Episodic Memory, -0.6 -0.6 Executive Function, Attention, Language and Global -0.7 -0.7 Cognition Baseline 18 months 36 months 54 months Baseline 18 months 36 months 54 months Latent growth curve models were conducted to evaluate the Timepoint Timepoint relation between baseline plasma cortisol and Aβ levels, other risk factors, and cognitive composite scores over the 72-month study period.  Summary In cognitively healthy older adults, high plasma cortisol levels are associated with greater decline in global cognition, and ac celerate the effect of Αβ+ on decline in global cognition, episodic memory, and attention over a 54-month period. These results suggest that therapies targeted toward lowering plasma cortisol and Αβ levels may help mitigate cognitive decline in the preclinical phase of AD.  Acknowledgements AIBL is a large collaborative study and a complete list of contributors can be found at our website www.aibl.csiro.au. We thank all who took part in the study. This research is supported by the Science and Industry Endowment Fund.

Xanamem  development: proposed study design XanADu – Phase II double blind, randomised, placebo-controlled study to assess the efficacy of Xanamem™ in participants with mild AD 220 Co-primary end points Treatment course ADAS-Cog 12 weeks ADCOMS + Mild Alzheimer’s patients Secondary Being trialled in Final Xanamem ™ end-points AUS, USA dosage for XanADu, to be confirmed Multiple: MMSE and UK CDR- SOB, RAVLT, NPI, NTP & CSF Aẞ and Tau ADCOMS: AD Composite Score. Wang et al., 2016. J. Neurol. Neurosurg. Psychiatry 0:1-7. Clinicaltrials.gov: NCT02727699. 12