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Safety and Efficacy 31 Week Data of Anavex 2-73 in a Phase 2a Study in Mild-to-Moderate Alzheimer’s Disease Patients

Steve Macfarlane1, Marco Cecchi2, Dennis Moore2, Paul Maruff3, Kristina M Capiak4, Christopher U Missling4

1 Caulfield Hospital, Melbourne, Australia; 2 Neuronetrix, KY, USA; 3 Cogstate, Melbourne, Australia, 4 Anavex Life Sciences Corp., New York, USA

PART A: Bioavailability Adaptive Cross-Over Design and PART B: 52-Week Voluntary Extension

MMSE ANAVEX 2-73 Alone vs with Donepezil

ANAVEX 2-73 Improves Components of Cogstate Tasks

Conclusions

§  Given unequal sample size, data after stratification are considered preliminary

§  Similar effect on MMSE in both MCI and Mild-to-Moderate AD patients

§  ANAVEX 2-73 treatment demonstrates reduction in overall HAM-D score after 31 weeks

Despite the relatively small sample size of this proof-of-concept, randomized, open-label study with oral daily doses (not optimized) of ANAVEX 2-73 ranging from 10mg to 50mg, data seems to indicate a converging and consistent response for all measurements (MMSE, ADCS-ADL, Cogstate, EEG/ERP) currently throughout 31 weeks (7 months) of ANAVEX 2-73 treatment. Patient retention rate at week 31 is 84%. Data suggest that treatment of ANAVEX 2-73 demonstrates reduction in overall HAM-D score after 31 weeks, notably through reductions in insomnia, anxiety and agitation. 17-week data (12-week PART B including 5-week PART A) as well as 31-week data (26-week PART B including 5-week PART A) of all available patients demonstrate that ANAVEX 2-73 preserves average MMSE and ADCS-ADL (PART B) scores across the entire patient group. In a disease state where progression is invariable over time, a stable MMSE and ADCS-ADL score is considered a positive outcome. When the group is tentatively stratified into mild-to-moderate and MCI (mild cognitive impaired) AD patients, no significant difference was observed within the MMSE or the ADCS-ADL (PART B) score, respectively. Likewise, when tentatively stratified between ANAVEX 2-73 alone and ANAVEX 2-73 PLUS donepezil administration, no significant difference was observed within the MMSE or the ADCS-ADL (PART B) score, respectively. Given the small sample size, this trend would require confirmation in a larger study. For cognitive assessment using the Cogstate test batteries, ANAVEX 2-73 continues to show benefits over baseline at 17 weeks and 31 weeks. ANAVEX 2-73 related improvement in psychomotor function, attention and working memory are preserved through 17 weeks and 31 weeks of treatment. Repeated-measures ANOVA reveals that Cogstate values maintained the baseline values through week 31. Mathematical modeling of the pharmacodynamic results is in progress. ANAVEX 2-73 is well tolerated and patients have requested to continue on the study drug, hence a further study extension after PART B has been granted. This will permit continued collection of longitudinal safety data on ANAVEX 2-73 for up to 3 years. The 17-week and 31-week data supports the plan to prepare for a larger, double-blind, placebo-controlled study of ANAVEX 2-73 in Alzheimer’s disease patients.

MMSE

PART B: §  Given unequal sample size, data after stratification are considered

preliminary §  Similar ADCS-ADL score and no notable difference between

exploratory analysis of ANAVEX 2-73 alone and ANAVEX 2-73 with donepezil (DPZ)

Over 31 weeks of treatment, ANAVEX 2-73 was associated with a sustained benefit in psychomotor function, attention and working memory. The specificity and consistency of these benefits suggest that ANAVEX 2-73 can sustain activation of attentional and working memory functions with repeated dosing in Alzheimer’s disease.

ADCS-ADL MCI and Mild-to-Moderate Patients

ADCS-ADL

PART B: §  Quality of life score ADCS-ADL (Activities of Daily Living) was

maintained through week 31 §  ADCS-ADL-Δ-scores were also maintained at a constant level

through week 31 and effects were confirmed with Bayesian inference calculations

§  In a disease state where progression is invariable over time, a stable ADCS-ADL score is considered a positive outcome

PART B: §  Given unequal sample size, data after stratification are considered

preliminary §  Similar ADCS-ADL score effect between MCI and Mild-to-Moderate AD

patients

Hamilton Depression Rating Scale (HAM-D) 31 Weeks ANAVEX 2-73 Effect on Synaptic Networks and Effect on Cognition and Behavior

EEG/ERP: ANAVEX 2-73 Rescues Cognitive Effects on a Cellular Level

1.  ERP  peak  measures  (P300):  fundamental  measures  of  synap;c  network  performance  

2.  ERP  target  detec;on  task  measures:  direct  measures  of  aAen;on,  speed  of  brain  processing,  and  simple  behavioral  performance  

3.  Psychometric  measures  (Cogstate)  cogni;ve  measures:  Detec;on:  processing  speed  (psychomotor  func;on),  Iden;fica;on:  reac;on  ;me  (aAen;on),  One  Back:  working  memory  (cogni;on),  One  Card  Learning:  visual  learning  (visual  memory),  ISLT:  verbal  learning,  ISLT-­‐delay:  verbal  memory    

4.  Psychometric  measures  (MMSE):  cogni;ve  measures  

5.  Behavioral  measures  (ADCS-­‐ADL):  behavioral  measures  

§  Each  of  these  metrics  measures  a  higher  level  of  brain  func;on  

EEG/ERP peak measures (P300)

ERP target detection task measures

Cogstate: Cognitive measures

MMSE: Cognitive measures

ADCS-ADL: Behavioral measures

Efficacy Data Measurements Cognition and Function §  Cognitive measures (MMSE); (Cogstate battery) §  Functional measures (ADCS-ADL)

Supportive Biomarker Measurements §  ERP (P300): fundamental measures of synaptic network performance and target engagement §  ERP target detection task measures: direct measure of attention, speed of brain processing, and

simple functional performance

Background This proof-of-concept study of 32 patients with mild-to-moderate Alzheimer’s disease (AD) demonstrated a favorable safety and tolerability/risk profile for ANAVEX 2-73, which activates the stress-reducing and survival protein, the Sigma-1 receptor. Presented here is preliminary exploratory efficacy data through 31 weeks (26-week PART B including 5-week PART A) from the randomized (into different treatment regimes) open-label study with ANAVEX 2-73 oral daily dosing ranging from 10mg to 50mg (not optimized in PART B). Further analysis will be performed.

§  MMSE mean scores maintained over 31 weeks §  Statistical analysis of MMSE revealed no other grouping factors (sex,

ApoE4, age, donepezil, baseline value) influencing the analysis §  Statistical analyses also revealed overall Δ-MMSE-scores

maintained at the same level and effects were confirmed with Bayesian inference calculations

§  In a disease state where progression is invariable over time, a stable MMSE score is considered a positive outcome

MMSE MCI and Mild-to-Moderate Patients

§  Given unequal sample size, data after stratification are considered preliminary

§  Similar MMSE score effect and no notable difference between exploratory analysis of ANAVEX 2-73 alone and ANAVEX 2-73 with donepezil (DPZ)

ADCS-ADL ANAVEX 2-73 Alone vs with Donepezil

Improved  Items  of  HAM-­‐D   Scored  Improvement  Count     in  [%]  

Insomnia   8   29%  Work  and  ac;vi;es   6   21%  

Anxiety  (psychic  and  soma;c)   5   18%  

Agita;on   4   14%  Depressed   4   14%  Insight   3   11%  Hypochondriasis   2   7%  Loss  of  libido  or  other  genital  symptoms   2   7%  Guilt   1   4%  Total   28  

Reduction of Insomnia, Anxiety and other Symptoms

Part B Part A PK - Study Extension

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AV2-73 AV2-73 PLUS DPZ

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MMSE Baseline 24 to 28 MMSE Baseline 16 to 23

(MCI) (Mild-Mod)

0.0 5.0

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Week 0 Week 5 Week 17 Week 31

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Baseline 31 week

HA

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Cogni&ve)decline))))))))))))))))))))))))))))))))))))Cogni&ve)improvement))

Magnitude)of)change)from)baseline)(d))

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*"p<0.05"

# Inclusive of all data entries received after November 7th 2015

80% 85%

104%

66%

29%

82%

93%

60%

-4%

43%

31% 37%

P300$Amplitude$ Task$Accuracy$ False$Alarms$ Reac7on$Time$

5 week

17 week

31 week

#!Cecchi!et!al,!Alzheimer's!&!Demen4a:!Diagnosis,!Assessment!&!Disease!Monitoring,!2015!

Baseline$ 5$Week$ 17$Week$ 31$Week$ Healthy$Control#$

P300$Amplitude$(μV)$ 5.99±0.58$ 7.09±0.72$ 6.38±0.61$ 5.93±0.77$ 7.36±0.39$

Task$Accuracy$$(%)$ 83.8±3.9$ 92.6±2.4$ 92.2±3.9$ 88.1±4.4$ 94.1±1.1$

False$Alarms$(%)$ 3.4±1.0$ 1.0±0.5$ 1.2±0.9$ 2.6±1.2$ 1.1±0.2$

ReacFon$Time$(ms)$ 559.0±24.0$ 492.6±23.8*$ 498.9±24.8$ 521.8±28.1$ 458.6±11.4$

Data$are$mean$±$SEM$*p<0.0007$

Baseline$

Healthy$Control#$

Rescue

$(%)$

20$

60$

40$

80$

Improvement$

Decline$

*

*p<0.0007$

#