Actinogen Medical Limited · ASX:ACW
Actinogen Medical — CTAD 2016
15 slides from Actinogen Medical's conference presentation, Dec 9, 2016
Slide 1: Xanamem: an 11ß-HSD1 Inhibitor in current development for the management of Alzheimer's disease
XanamemTM: an 11ß-HSD1 Inhibitor in current development for the management of Alzheimer’s disease (AD) Ritchie CW* for Cummings J, Masters CL, Maruff P, Ketelbey B, Webster S, Seckl J, Ruffles V and Walker B. *Prof Craig W Ritchie Director of Centre for Dementia Prevention Centre for Clinical Brain
Slide 2: Disclosures
Disclosures • I have been supported for travel to this meeting by Actinogen who I also have a consultancy arrangement with through the University of Edinburgh. • I have also provided paid consultancy work over the last 5 years for: – AbbVie, Eisai, Sanofi-Aventis, Merck, Janssen, Nutricia, Novartis,
Slide 3: Presentation Overview
Presentation Overview 1. Role of HPA Axis and Cortisol in Alzheimer’s disease 2. Mechanism of action, pre-clinical and clinical work with central 11b-HSD-1 Inhibition 3. The Xanadu Study of XanamemTM in Mild Alzheimer’s Dementia
Slide 4: Elevated circulating cortisol levels may contribute to AD pathogenesis
Elevated circulating cortisol levels may contribute to AD pathogenesis(1,2). • Direct: [1] increase levels of amyloid precursor protein (APP) and BACE leading to increased Ab42 formation [2] reduced Ab42 degradation via attenuation of insulin degrading enzyme(3) • Indirect: [1] Insulin resistance, [
Slide 5: Plasma cortisol, brain amyloid-b, and cognitive decline in preclinical Alzheimer's disease
Plasma cortisol, brain amyloid-b, and cognitive decline in preclinical Alzheimer’s disease: a 6-year prospective cohort study 1 1 Pietrzak RH et al., Biological Psychiatry, Cognitive Neuroscience and Neuroimaging (ePrint) 2016 METHOD •Cognitively normal older adults (n=416) enrolled in the AIBL stud
Slide 6: Results
RESULTS •High baseline plasma cortisol levels associated with 2.2 times the risk of Αβ+ and associated with greater decline in global cognition (Cohen’s d=0.42), episodic memory (Cohen’s d=0.69), and attention (Cohen’s d=0.31)*. •*Effects were independent of age, education, premorbid intelligence, A
Slide 7: Function of 11b-HSD1
Function of 11b-HSD1 ACTIVE INACTIVE
Slide 8: Methods
METHODS Short Term Study: 14 month old mice: UE2316 10mg/kg/d through SC route (n=20 1:1 active:placebo) Long Term Study: 6-7 month old mice fed UE2316 (n=32) or control diet (n=16) for up to 57 weeks Behaviour: Memory in Passive Avoidance, Y-Maze Testing, Open Field Testing, Spontaneous Alteration
Slide 9: 11b-HSD1 Inhibition in TG2476 Mice
11b-HSD1 Inhibition in TG2476 Mice Selected Behavioral Improvements Reduced Amyloid Plaque Burden Impact of 11b-HSD-1 inhibition on [A] Impact of 11b-HSD-1 inhibition on [A] Open field [B] Spontaneous Alteration Short Term Plaque Number, [B] Short and [C] Morris Water Maze term Plaque Area and [C] L
Slide 10: Carbenoxolone double-blind placebo crossover studies
In two double-blind, placebo RCT crossover studies, carbenoxolone •Improved verbal fluency (P < 0.01) after 4 weeks n=10 elderly men (aged 55–75 y) •Improved verbal memory (P < 0.01) after 6 weeks n=12 type 2 diabetics (52–70 y). Sandeep et al. 11-Hydroxysteroid dehydrogenase inhibition improves cog
Slide 11: Summary of Background
Summary of Background • Strong biological basis for aetiological role of elevated central cortisol in AD pathology. • Epidemiological work associates elevation of cortisol with AD pathology and clinical progression • Interventions studies in pre-clinical and clinical models with 11- bHSD1 showing pr
Slide 12: XanADu (Xanamem in AD)
XanADu (Xanamem in AD) • A Phase II, Double Blind, 12-Week, Randomised, Placebo-Controlled Study to Assess the Safety, Tolerability and Efficacy of Xanamem™ in Subjects with Mild Dementia due to Alzheimer’s Disease • Primary objective: Performance of Xanamem™ from Baseline to end of treatment compar
Slide 13: XanADu (Xanamem in AD)
XanADu (Xanamem in AD) • Key subject inclusion criteria includes: – Mild dementia due to Alzheimer’s disease – MMSE 20 to 26 (inclusive) – CDR of 0.5 to 1.0 – On a stable dose of acetylcholinesterase (AChEI) and/or memantine (at least 3 months prior to Screening) OR treatment- naïve. Initiating AChE
Slide 14: XanADu (Xanamem in AD)
XanADu (Xanamem in AD) • Initiating in US, Australia and UK in 2017 • 174 patients with mild Alzheimer’s dementia to be randomised • Excellent PK and Brain Penetrance to achieve optimal central 11b-HSD1 inhibition with no/minimal peripheral effects
Slide 15: Summary
Summary • Epidemiological, biological and (limited) trial evidence associates elevations in cortisol with Alzheimer’s disease and clinical progression. • 11b-HSD1 Inhibition is a targetable and rational approach to symptomatic and disease modification in Alzheimer’s disease. • The XanADu study is th