Actinogen Medical Limited · ASX:ACW
Actinogen Medical — AAT-AD/PD 2020
38 slides from Actinogen Medical's conference presentation, Apr 3, 2020
Slide 1: Chronically Elevated Cortisol and Cognitive Impairment: Therapeutic Potential of Xanamem
CHRONICALLY ELEVATED CORTISOL AND COGNITIVE IMPAIRMENT: THE THERAPEUTIC POTENTIAL OF XANAMEM™, A POTENT INHIBITOR OF THE 11β-HSD1 ENZYME Authors: T. Miller1, C. Ritchie2, J.W. Ketelbey1; 1Australia, 2United Kingdom Presented by Prof Craig W Ritchie Director of Centre for Dementia Prevention Centre f
Slide 2: Disclosures
Disclosures Provided paid consultancy over the last 8 years for: Actinogen, Allergan, Biogen, Eisai, Alector, Janssen, MSD, Nutricia, Lundbeck, Prana Biotechnology, Abbvie, Roche, Eli Lilly, GSK, and Pfizer Co-lead the EPAD Consortium - a public:private partnership with several pharmaceutical compan
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 in 11β-HSD-1 Inhibition 3. Update on results for the XanADu study 4. Update on results for the XanaHES study 5. Update on results for the Target Occupancy studies 6. P
Slide 4: Role of HPA Axis and Cortisol in Alzheimer's disease
Role of HPA Axis and Cortisol in Alzheimer’s disease
Slide 5: HPA Axis
HPA Axis In normal circumstances, the CRF A released by the hypothalamus activates A B ACTH release by the pituitary gland, which stimulates the adrenal glands to secrete cortisol. Cortisol inhibits its own secretion via a negative feedback loop. The hippocampus inhibits the hypothalamo-pituitary-ad
Slide 6: Elevated circulating cortisol may contribute to AD pathogenesis
Elevated circulating cortisol may contribute to AD pathogenesis(2,3) Direct: 1. Increased levels of amyloid precursor protein (APP) and BACE leading to increased Aβ42 formation2,3,4 2. Reduced Aβ42 degradation via attenuation of insulin degrading enzyme5 Indirect: 1. Insulin resistance 2. Angiopathi
Slide 7: Plasma cortisol, brain amyloid-β, and cognitive decline in preclinical Alzheimer's disease
Plasma cortisol, brain amyloid-β, and cognitive decline in preclinical Alzheimer’s disease: a 6-yr prospective cohort study10 Methods: Cognitively normal older adults (n=416) enrolled in the AIBL study underwent Aβ neuroimaging at a single timepoint. Fasted cortisol were dichotomized using a media
Slide 8: 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) attention (Cohen’s d=0.31) *Effects were independent of age, education, premorbid intelligence, APOE
Slide 9: Mechanism of action, pre-clinical and clinical work in 11β-HSD1 inhibition
Mechanism of action, pre-clinical and clinical work in 11β-HSD1 inhibition
Slide 10: Function of 11β-HSD1
Function of 11β-HSD1 ACTIVE INACTIVE Xanamem™ reversibly binds to the 11β-HSD1 enzyme, inhibiting this reaction, preventing the conversion of inactive cortisone into the active cortisol 10
Slide 11: Pre-Clinical Literature
Pre-Clinical Literature 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 Behavior Memory in Passive Avoidance, Y-Maze Testing, Open Field Testi
Slide 12: Inhibition of 11β-HSD1 enhances cognition in AD-prone mice
Inhibition of 11β-HSD1 enhances cognition in AD-prone mice After 39 weeks of treatment, UE2316-treated mice After 52 weeks of treatment, UE2316-treated mice (n=9) (n=23) exhibited a significant increase in percentage exhibited significant decreases in latency to find the hidden alternation compared
Slide 13: Inhibition of 11β-HSD1 inhibits AD pathology in AD-prone mice
Inhibition of 11β-HSD1 inhibits AD pathology in AD-prone mice As shown by 6E10 antibody staining for Aβ, treatment with UE2316 for 29 days reduced amyloid plaque levels in the cortex (**ρ=0.002), amygdala (*ρ=0.05) and whole brain (ρ=0.01) compared with vehicle (n = 10). Via KS300 imaging software,
Slide 14: Clinical Literature
Clinical Literature 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). 12. Proc Natl Acad Sci USA. 2004;101:6734–6739 14
Slide 15: Summary of Background
Summary of Background Strong biological basis for aetiological role of elevated central cortisol in AD pathology Epidemiological work associate's elevation of cortisol with AD pathology and clinical progression Interventional studies in pre-clinical and clinical models with 11β-HSD1 shows prom
Slide 16: Update on results for the XanADu Study
Update on results for the XanADu Study
Slide 17: XanADu Phase II clinical trial
XanADu Phase II clinical trial Double-blind, randomised, placebo-controlled study to assess the efficacy and safety of Xanamem 10mg in subjects with mild Alzheimer's disease1 Xanamem treatment course 186 patients with mild 12 weeks Alzheimer’s disease2 Trial conducted at 25 sites in 10mg daily Xanam
Slide 18: XanADu endpoints
XanADu endpoints XanADu’s results inform future clinical development XanADu: primary and secondary efficacy endpoints1 ADAS- ADCOMS COG14 Primary and secondary endpoints CDR- SOB MMSE were not met with 10mg QD Xanamem RAVLT NTB for 12 weeks Primary NPI Secondary 1. ADAS-COG14: Alzheimer’s Disease As
Slide 19: XanADu results summary
XanADu results summary PD BIOMARKER XANAMEM MEAN PLACEBO MEAN p VALUE CHANGE CHANGE FOR DIFFERENCE (Baseline to EOT) (Baseline to EOT) Significant ACTH 3.0 -1.0 <0.001 PD effects ANDROSTENEDIONE 0.22 -0.01 <0.001 DHEAS 42.4 -4.9 <0.001 CORTISONE 11.9 5.8 <0.001 SAFETY RESULTS XANAMEM PLACEBO TOTAL T
Slide 20: XanADu Study – Pharmacodynamic Results
XanADu Study – Pharmacodynamic Results Xanamem 10mg once-daily resulted in early and significant pharmacodynamic modulation of cortisol-related hormones throughout the 12-week study ACTH: 12 weeks treatment Androstenedione: 12 weeks treatment DHEA-S: 12 weeks treatment LS Mean Changes from baseline
Slide 21: Update on results for the XanaHES Study
Update on results for the XanaHES Study
Slide 22: XanaHES Phase I clinical trial
XanaHES Phase I clinical trial A Phase I, Single Blind, 12-Week, Randomised, Placebo-Controlled Study to Assess the Safety, Tolerability and Efficacy of Xanamem 20mg Daily in Healthy Elderly Subjects1 Xanamem treatment course 42 healthy elderly subjects 12 weeks (30 Xanamem : 12 Placebo) 20mg daily
Slide 23: XanaHES (Xanamem in Healthy Elderly Subjects)
XanaHES (Xanamem in Healthy Elderly Subjects) Primary objective: Safety and Tolerability of Xanamem™ compared to placebo Secondary objective: Analysis of Pharmacokinetic and Pharmacodynamic data via blood plasma and CSF Performance in the CogState neuropsychological test battery (NTB) of Xanamem™ Ex
Slide 24: XanaHES (Xanamem in Healthy Elderly Subjects) cont.
XanaHES (Xanamem in Healthy Elderly Subjects) cont. Initial study protocol was to escalate from 20mg to 30mg QD dosing, on a further 42 subjects, once 20mg was deemed safe and well tolerated: – However data from the concurrently-run PET Target Occupancy study revealed that escalation to 30mg would
Slide 25: Cogstate Neuropsychological Test Battery (NTB)
Cogstate Neuropsychological Test Battery (NTB) Test Simple Description Cognitive Domain Primary Outcome Detection (DET) Has the card turned over? Simple Reaction Time Log10 Reaction Time (lmn) Identification (IDN) Is the card red? Attention Log10 Reaction Time (lmn) Have you seen this card One Card
Slide 26: XanaHES (Xanamem in Healthy Elderly Subjects) cont.
XanaHES (Xanamem in Healthy Elderly Subjects) cont. Working memory (One Back Test) Visual attention (Identification Test) Psychomotor function (Detection Test) Strongly statistically Statistically Good trend to significant result significant result a positive result Score Score Score P<0.01 P=0.05 P
Slide 27: XanaHES (Xanamem in Healthy Elderly Subjects) cont.
XanaHES (Xanamem in Healthy Elderly Subjects) cont. XanaHES 20mg Cogstate Cognitive Test Battery: p values and Cohen’s d effect size Cognitive Evaluation (Test) p value Treatment Effect Size: Cohen’s d All Male Female Week 2 Week 4 Week 8 Week 12 Working Memory <0.01* <0.01* 0.03* 0.64# 0.78# 0.64#
Slide 28: Update on results for the Target Occupancy Studies
Update on results for the Target Occupancy Studies
Slide 29: Target Occupancy Study
Target Occupancy Study Target Occupancy Project with 11β-HSD1-specific PET tracer: Pre-Clinical toxicology of the tracer performed in-vitro autoradiography and human tissue homogenate binding studies performed to quantify Kd, Vmax, and enzyme activity; results are being collated and will be pres
Slide 30: Target Occupancy Study: preliminary results
Target Occupancy Study: preliminary results Phase I target occupancy study demonstrates that 5mg to 30mg Xanamem significantly occupies the 11β-HSD1 enzyme throughout the brain 50% to 85% occupancy, dependent upon brain region, dosage and study subject1 Additional ongoing cohorts at TBC: do we have
Slide 31: Plans for next AD study: Xanamem in MCI due to Alzheimer's disease
Plans for next AD study: Xanamem in MCI due to Alzheimer’s disease
Slide 32: MCI in Alzheimer's disease
MCI in Alzheimer’s disease Actinogen plans to evaluate Xanamem in patients with Mild Cognitive Impairment as part of the next phase of studies, linking the XanaHES results with Alzheimer’s disease Healthy elderly Mild Cognitive Mild Moderate Severe Impairment (MCI) (20mg daily) (10mg daily) Alzheime
Slide 33: Additional therapeutic indications for Xanamem in planning
Additional therapeutic indications for Xanamem in planning
Slide 34: Multiple diseases associated with chronically raised cortisol
Multiple diseases associated with chronically raised cortisol Phase I and II safety and efficacy data positions Xanamem for trialling in other indications associated with chronically raised cortisol and cognitive impairment. Actinogen planning to initiate trials in: Cognitive impairment associated
Slide 35: Summary
Summary
Slide 36: The therapeutic potential of Xanamem, a potent inhibitor of the 11β-HSD1 enzyme
The therapeutic potential of Xanamem, a potent inhibitor of the 11β-HSD1 enzyme Epidemiological, biological, and current body of evidence associates chronic elevation of cortisol with development and progression of Alzheimer’s disease The XanaHES safety study confirmed a robust efficacy signal a
Slide 37: Special thanks
Special thanks Bill Ketelbey, CEO & Managing Director Actinogen Medical Tamara Miller, VP of Drug Development & Strategy Actinogen Medical Chris Rowe and Victor Villemagne, Austin Hospital Linear Clinical Research Gifford Biosciences Cogstate Colin Masters and Jeff Cummings – Xanamem C
Slide 38: Thank You
Thank You Collaborators Investigators Research Participants