CTAD, December 4-7, 2019

Novel analytics framework for augmenting single-arm Phase 2a open label trials with Real-World external control data: Application to the Blarcamesine (ANAVEX®2-73) study in Alzheimer’s disease matched

with propensity corrected patients from Alzheimer’s Disease Neuroimaging Initiative (ADNI) exploring treatment effect on cognition

at interim two-year (104-Week) time point

Mohammad Afshar, MD, PhD¹; Coralie Williams, MSc¹; Nanthara Sritharan, MSc¹; Frédéric Parmentier, PhD¹; Adrien Etcheto, MSc¹; Christopher U Missling, PhD²

¹Ariana Pharma, Paris, France²Anavex Life Sciences Corp., New York, NY

Nasdaq: AVXL | DEC 2019

▪ MA is an employee and shareholder of Ariana Pharmaceuticals

▪ CW, NS, FP, AE and are employed by Ariana Pharmaceuticals

▪ CM is an employee and shareholder of Anavex Life Sciences

Disclosures

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FDA’s new Real World Evidence Program Likely to have a Profound Impact on the Biopharma Industry

RWD

Pharma data (observational)

Lab/biomarkersdata

Mortalitydata

Social media data

Pharmacy

data

Hospital

data

Survey

data

Electronics

medical and health

records

Diseaseregistries

Consumer data

Mobile & Device

Imagerydata

Genomics

data

https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence

RWE report released

December 2018From Real-World Data (RWD)

to Real-World Evidence (RWE)

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Real World « Synthetic » Control Arms

• High quality curated electronic health record (EHR) data collected during

routine clinical care of patients have the potential to accelerate drug

development

• In areas of high unmet need, real world controls could help provide

external control for regulatory decision making

• Requires advanced analytical techniques to address limitations pertaining

to RW data (propensity scores)

• « Real world patients » may be different to patients enrolled in clinical

trials (comorbidities, etc.) and use of RW data may provide a more

accurate picture of the impact of a novel therapy

• Collection of real-world data is not new

• May provide access to patients that may not have been considered in a

clinical trial

• Ethical question of unnecessarily exposing patients to placebo

• Reducing size, duration and costs of trials

• Accelerating regulatory path

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Use of Real World Evidence in Regulatory Settings is Gaining Momentum

Comparative

evidence and

complete RCTsEconomical benefits

Complete description

of a patient's

pathway to disease

Regulatory

acceleration

Example : Evaluating results from a Phase 2 single arm study for

the approval of Blinatumomab in the treatment of advanced acute

lymphoblastic leukemia is complemented with Real World controls

FDA granted accelerated approval to Blinatumomab (Blincyto,

Amgen) for the treatment of adult and pediatric patients with B-cell

precursor acute lymphoblastic leukemia

March 29, 2018

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Meta analysis and comparison to Standard of Care (SoC)

depends upon similarities in study populations and definitions of

outcomes. Heterogeneity across studies presents difficulties in

how to interpret outcomes

Matched‐pair analysis using a propensity score:

• Selects for comparable patients between historical and

baseline clinical datasets based on predefined variables

• Data are more precisely comparable to the patient population

receiving the new therapy

• Increased robustness

Method used for Identifying Matching Patients at Baseline Propensity Score Matching Superior to Meta Analysis

Propensity Scoring

• Predicted probability of treatment, given what we know about the patient’s confounding factors

• Goal: Create balance at inclusion in order to remove confounding effect and thus lead to causally

interpretable evaluation of treatment effect

Matched‐pair

analysis using a

propensity score

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Alzheimer’s Disease Neuroimaging Initiative (ADNI) Provides an Opportunity for Patient Level Matching

N=901subjects with mild cognitive

impairment (EMCI, LMCI and MCI)

diagnosis at baseline

DNAWES

RNAWES

Outcome

ScoresBaseline

Baseline MMSE Outcome Scores

Evolution in time

Change and rate of decline

in MMSE

Clinical

Physical examination,

Vital signs, Concomitant

medication, Cognitive

and Behavioral

Scores…WES: Whole Exome Genomic Sequencing

N=345subjects with Alzheimer disease

(AD) diagnosis at baseline

N=519cognitively normal (CN)

subjects at baseline

N=106subjects with significant memory

concern (SMC) at baseline

AD=45 SMC=0

CN=273MCI=471

2) Integration of all available data in ADNI1) Real-world longitudinal

data of 1891 subjects

SUBJECTS WITH AVAILABLE

GENOMIC DATA :

AD=266 SMC=89

CN=392MCI=795

SUBJECTS WITH >2 MMSE

MEASURES OVERTIME:

Data used

in analysis

Data used in analysis

8

Extensively Characterized single arm Phase 2a Clinical Study Investigating ANAVEX®2-73 in Alzheimer’s Disease Patients Provides a unique Precision Medicine Framework

Dose and Concentration of Blarcamesine (ANAVEX®2-73)

DNAWES

RNAWES

Outcome Scores

Baseline

MMSE ADCS-ADLCOGSTATEEEG/ERPHAM-D

Outcome Scores

Evolution in time

Change since baseline and rate of decline in:

MMSEADCS-ADLCOGSTATEEEG/ERPHAM-D

Clinical

Physical examination, Vital signs, Concomitant

medication, Medical history, Cognitive and

Behavioral Scores…

==

WES: Whole Exome Genomic Sequencing

Gut

Microbiota

N=32 N=21N=24N=30 N=21

Trial no.: NCT02244541 Trial no.: NCT02756858Cohort characteristics:32 Mild-moderate AD patients• Age range: 55 to 85• Clinically diagnosed with

MRI and/or PET scans Extension administration of ANAVEX®2-73 (Weeks 5 to 265):Oral once daily: 10 mg, 20mg, 30mg, 40mg, 50mg

Ariana’s KEM® Artificial Intelligence:▪ Systematic integrated analysis of all combined parameters

▪ Identifies patient sub population benefiting from drug

▪ Enables design of fast track trial

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ANAVEX®2-73 Selective Sigma-1 Receptor (SIGMAR1) Agonist Demonstrated Improved MMSE1 and ADCS-ADL2 Scores in Phase 2a AD Study through 148 Weeks

Source:

Hampel H., Afshar M., Parmentier F. et al., CTAD 2018;

Hampel et al., 2019, Alzheimer’s & Dement [under review]

1 Mini Mental State Examination (MMSE)2 Alzheimer’s Disease Cooperative Study Group - Activities of Daily Living Inventory (ADCS-ADL)

Adju

ste

d c

hange in A

DC

S-A

D2

(±SE

)

Adju

ste

d c

hange in M

MS

E1

(±SE

)

p-value < 0.0001 p-value < 0.0008

N=8

N=13

N=8

N=13

10

• Sigma-1 receptor (SIGMAR1) serves as an intracellular chaperone and functional modulator of

calcium homeostasis and synaptic plasticity through targeting neuro-inflammation, protein-

misfolding, beta amyloid, hyper-phosphorylated tau, oxidative stress, mitochondrial dysfunction

and cellular stress

• Numerous studies demonstrated the beneficial effects of SIGMAR1 agonists on neuro-

inflammation1,2,3

ANAVEX®2-73 Mechanism of Action: SIGMAR1 Restores Homeostasis Caused by Neuro-inflammation and Protein Misfolding

1) Jia J et al 2018. Front Cell Neurosci. 2018 Sep 20;12:314; 2) Zhao J et al 2014. Invest. Ophthalmol. Vis. Sci. 55, 3375–3384

3) Behensky AA et al 2013. J. Pharmacol. Exp. Ther. 347, 458–467; 4) Cenci A et al 2016. Presented at World Parkinson Congress

5) Hall H et al 2018. Alzheimers Dement. Jun;14(6):811-823; 6) Allahtavakoli M et al 2011. Brain Res Bull. May 30;85(3-4):219-24

7) Cogram P et al 2016. Presented at Gordon Research Conference; 8) Lisak RP et al 2016. Poster presentation at ACTRIMS

9) Lisak RP et al 2017. Oral presentation at ECTRIMS

ANAVEX®2-73 reduces microglia over-activation

ANAVEX®2-73 significantly decreased the expression

of CD68 (marker of activated microglia) in the

substantia nigra in a model of Parkinson's disease4

CD68 cell count

• The SIGMAR1 agonist ANAVEX®2-73 could potentiallynormalize neuroinflammatory processes by several differentmechanisms:1. Reducing microglia over-activation4

2. Reducing inflammatory cytokines5

3. Increasing anti-inflammatory cytokines6

4. Releasing protective factors, e.g. BDNF7

5. Protect against inflammatory molecules8,9

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Simulating a Controlled Clinical Trial: Match Patients at Baseline with Propensity Score Matching (PSM)

The propensity score matching (PSM) methodology:

PSM attempts to reduce the bias due to confounding variables that could be found in an estimate of

the treatment effect obtained from simply comparing outcomes among units that received the

treatment versus those that did not. Replace the collection of confounding covariates with one scalar

function of these covariates.

Age at baseline

Sex

MMSE score at baseline

SIGMAR1 p.Q2P

Education (years)

…..

Logistic Regression

Propensity score

[0, 1]

Variety of matching options with:

• Caliper: A caliper is the distance which is acceptable for any match. A caliper of 0.25 means that all matches not equal to or within 0.25 standard deviation of the logit of the

propensity score of each covariate in X are dropped.

• With or without replacement: indicates whether or not replacement is allowed during matching.

• Ties: indicates whether ties are allowed or not i.e. If one treated observation matches more than one control observation

ADNI AD patients

N = 345

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Analysis Steps: Matching Patients at Baseline

ANAVEX AD patients treated with

ANAVEX®2-73

N = 32

Analysis cohort:

N = 45 AD patients

with genomic data

300 ADNI AD patients did not

have SIGMAR1_p.Q2P

information

Propensity Score Matching

using:

- MMSE at baseline

- AGE at baseline

- APOE4

- GENDER

- EDUCATION

- SIGMAR1 p.Q2P

Matched at Baseline:21 patients ANAVEX21 patients ADNI

Analysis cohort:

N = 21 AD patient

with genomic data

11 Anavex treated patients did

not have SIGMAR1_p.Q2P

information

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APOE ε4+ Allele Distribution in ANAVEX®2-73 Study

High ANAVEX®2-73

concentration

Cohort

Low ANAVEX®2-73

concentration

Cohort

6 out of 8 patients

75% APOE ε4+ carriers in

High ANAVEX®2-73 concentration

cohort

4 out of 13 patients

30.7% APOE ε4+ carriers in

Low ANAVEX®2-73 concentration

cohort

→ APOE ε4+ carriers are 2.4 times more frequent in the High ANAVEX®2-73

concentration cohort compared to Low ANAVEX®2-73 concentration cohort

→ Since APOE ε4+ carriers worsen quicker in AD, hence, no “preference” to

High ANAVEX®2-73 concentration cohort

ADNI AD matched

Cohort

10 out of 21 patients

48% APOE ε4+ carriers in

ADNI AD matched cohort

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LME model (3-arms): Alzheimer’s Disease Patients with high Concentration of ANAVEX®2-73 MMSE Performance better over 104 Weeks vs matched ADNI AD Cohort (p-value < 0.01)

Adju

ste

d M

ean c

hange in

MM

SE

fro

m b

ase

line

(±

SE

)

Time (Weeks)

Cohort of high ANAVEX®2-73 concentration

cohort shows significantly smaller decline in

MMSE (-1.1) compared to ADNI AD matched

cohort (-4.4) at Week 104

Cohort of low ANAVEX®2-73 concentration shows slightly

smaller decline in MMSE (-3.9) compared to ADNI AD

matched cohort (-4.4) at Week 104

Covariates included in the MMRM-LME model for MMSE change are: time as continuous, cohort

group (ANAVEX2-73 concentration, High, Low/Med or ADNI), APOE ε4 status, age (Low, High),

baseline MMSE score, SIGMAR1-Q2P variant, interactions between time and cohort group, time

and APOE ε4 status, time and SIGMAR1, and concentration group and SIGMAR1 variant.

p-value < 0.01

N=8

N=21

N=13

ADNI AD matched patients

Extrapolated adjusted slope based on LME model of change in

MMSE beyond 104-weeks (using all available data)

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Conclusions

• Small, data rich, AI-driven adaptive single arm precision medicine clinical

studies as designed to assess ANAVEX®2-73 efficacy may be a template

for future studies investigating CNS drugs in order to rapidly explore novel

mechanism of action, before engaging in larger trials

• Propensity matched real world evidence experiment using ADNI

shows efficacy of patients with high ANAVEX®2-73 concentration vs

synthetic control arm at week 104 (p<0.01)

• Limitations:

• Comparative ADNI data available only up to 104 weeks

• Number of genetically characterized patients in comparative ADNI data

• MMSE cognition score to match patients

• Hence: Randomized placebo-controlled ANAVEX®2-73 Phase 2b/3

study currently underway with 450 early Alzheimer’s disease patients

• Additionally: Gut microbiota species identified as linked to ANAVEX®2-73

response consistent with the interaction of SIGMAR1 and the gut-brain

axis and inflammatory mechanisms (CTAD 2019 poster)

• Human Clinical Data –

ANAVEX®2-73 Phase 2a

study in Alzheimer’s disease

with favorable safety and

exploratory efficacy results

through 148 weeks

• Phase 2a study

demonstrated significant

ANAVEX®2-73 effect of

concentration on efficacy

(Hampel et al., 2018) and

identified a genomic

biomarker of response

SIGMAR1 &

ANAVEX®2-73

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• Principal Investigators & clinical sites’ study staff

• Data safety review committee

• Anavex SAB

• Most of all, grateful acknowledgement of the contribution of the participating AD patients and

their caregivers

Acknowledgements

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