Longitudinal148-WeekUpdateofANAVEX®2-73Phase2aAlzheimer’sDiseaseExtensionStudy

CTAD October 2018

Harald Hampel, MD, PhD1, Mohammad Afshar, MD, PhD2, Frédéric ParmenBer, PhD2, Coralie Williams, MSc2, Adrien Etcheto, MSc2, Federico Goodsaid, PhD3, Christopher U Missling, PhD4 1Department of Neurology, Sorbonne University, Paris, France; 2Ariana Pharma, Paris, France, 3Regulatory Pathfinders LLC, San Francisco, CA, 4Anavex Life Sciences Corp., New York, NY

Nasdaq: AVXL

Safe Harbor This presentaBon contains forward-looking statements made within the meaning of the Private SecuriBes LiBgaBon Reform Act of 1995 by Anavex® Life Sciences Corp. and its representaBves. These statements can be idenBfied by introductory words such as “expects,” “plans,” “intends,” “believes,” “will,” “esBmates,” “forecasts,” “projects,” or words of similar meaning, and by the fact that they do not relate strictly to historical or current facts. Forward-looking statements frequently are used in discussing potenBal product applicaBons, potenBal collaboraBons, product development acBviBes, clinical studies, regulatory submissions and approvals, and similar operaBng macers. Many factors may cause actual results to differ from forward-looking statements, including inaccurate assumpBons and a broad variety of risks and uncertainBes, some of which are known and others of which are not. Known risks and uncertainBes include those idenBfied from Bme to Bme in reports filed by Anavex Life Sciences Corp. with the SecuriBes and Exchange Commission, which should be considered together with any forward-looking statement. No forward-looking statement is a guarantee of future results or events, and one should avoid placing undue reliance on such statements. Anavex Life Sciences Corp. undertakes no obligaBon to update publicly any forward-looking statements, whether as a result of new informaBon, future events or otherwise. Anavex Life Sciences Corp. cannot be sure when or if it will be permiced by regulatory agencies to undertake clinical trials or to commence any parBcular phase of clinical trials. Because of this, statements regarding the expected Bming of clinical trials cannot be regarded as actual predicBons of when Anavex Life Sciences Corp. will obtain regulatory approval for any “phase” of clinical trials. We also cannot be sure of the clinical outcome for efficacy or safety of our compounds. PotenBal investors should refer to the risk factors in our reports filed on Edgar.

2

Disclosures §  The studies were funded by Anavex Life Sciences

§  HH serves as Senior Associate Editor for the Journal Alzheimer’s & DemenBa; he is the speaker of the Alzheimer Precision Medicine IniBaBve (APMI), he received lecture fees from Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the insBtuBon), travel funding from FuncBonal NeuromodulaBon, Axovant, Eli Lilly and company, and Oryzon Genomics, consultancy fees from Axovant, Anavex, Oryzon Genomics, FuncBonal NeuromodulaBon, and parBcipated in scienBfic advisory boards of FuncBonal NeuromodulaBon, Axovant, Eli Lilly and company, Oryzon Genomics, Roche DiagnosBcs

§  MA, FP, CW and AD are employees and shareholders of Ariana Pharma

§  FG is employee and shareholder of Regulatory Pathfinders

§  CM is an employee and shareholder of Anavex

3

Agenda

§  IntroducBon

§  Background

§  ANAVEX®2-73-003 Extension Study Update

§  Precision Medicine Paradigm from Oncology to Alzheimer’s Disease

§  KEM® plaporm to Select Relevant Biomarkers

§  Mixed-Effect Models for Repeated Measures with a Linear Time Component

4

IntroducBon

§  ANAVEX®2-73 is a novel compound relevant to AD and neurodegeneraBve, neurological diseases

§  TargeBng the Sigma-1 receptor (SIGMAR1)

§  SelecBve under pathological condiBons while sparing normal physiological acBvity, thus limiBng adverse side effects#

§  ANAVEX®2-73 is an orally available small molecule that acBvates SIGMAR1 which serves as an intracellular chaperone and funcBonal modulator of calcium homeostasis and synapBc plasBcity through targeBng protein-misfolding, oxidaBve stress, mitochondrial dysfuncBon, inflammaBon, cellular stress

#Nguyen et al. J Pharmacol Sciences 127 (2015) 17-29

5

Background §  ANAVEX®2-73 is a new targeted therapy in Alzheimer and other neurological diseases

§  57-week Phase 2a study: ANAVEX®2-73 was tested in a 57-week Phase 2a study (AV2-73-0021) with 32 mild-to-moderate Alzheimer’s disease demenBa paBents. This study showed:

−  ConcentraBon-dependent response in this populaBon for exploratory funcBonal (ADCS-ADL2) and cogniBve (MMSE3) endpoints

−  New AD paBent selecBon genomic biomarker variants of •  SIGMAR1 (rs1800866) •  COMT (rs113895332/ rs61143203)

−  These new paBent selecBon biomarkers enable a targeted therapy for paBents which are likely to benefit from ANAVEX®2-73

§  57-week Phase 2a study was extended by 208 weeks (AV2-73-0034) in 21 paBents

§  Update at 148-week of Phase 2a extension: The impact of these SIGMAR1 and COMT biomarkers on ANAVEX®2-73 response has been assessed at 148-week extension

2Mini Mental State ExaminaBon (MMSE) 3Alzheimer’s Disease Co-operaBve Study – AcBviBes of Daily Living Inventory (ADCS-ADL) 6

1,4 ClinicalTrials.gov IdenBfier: 1NCT02244541; 4NCT02756858

ANAVEX®2-73 acBvates Sigma-1 Receptor Restoring Cellular Homeostasis

Restoring Homeostasis and NeuroplasBcity

ANAVEX2-73

Source: SchemaBc approximaBon adapted from Miki et al, Dec 9. doi: 10.1111/neup.12080 Neuropathology 2013 Glembotski et al., CirculaBon Research. 2007;101:975-984

sBmulaBng cells to regain funcBonality & plasBcity

Sig-1R / σ1 = Sigma-1 Receptor BIP = Binding Immunoglobulin Protein

Chaperoning Misfolded proteins

Two-trans-membrane SIGMAR1 is an ER protein that resides in the mitochondrial assoc. ER membrane (MAM) Tanslocates to the cytosol/plasma membrane and interacts with numerous receptors, ion channels and proteins as determined via experimental means

7

Overview ANAVEX®2-73 Phase 2a Clinical Study

1, 2 ClinicalTrials.gov IdenBfier: 1NCT02244541; 2NCT02756858 *: 1 paBent is outside inclusion criteria. This paBent was excluded from calculaBons

21* 27* 32*

Part A PK: Iv and Oral

Part B Oral only

002 study1 003 study2 (extension)

Extension Oral only

Cross-over administraBon scheme

PaBent characterisBcs: - Mild-moderate AD paBents - Age range: 55 to 85 - Clinically diagnosed with MRI and/or PET scans

Part B extension administraBon of ANAVEX®2-73: Oral once daily: 10 mg, 20mg, 30mg, 40mg, 50mg

8

ANAVEX®2-73 Phase 2a Alzheimer Extension Study Safety Update

§  Safety update through 148 weeks:

§ ConBnued favorable safety and tolerability

§ No ANAVEX®2-73 related AE or SAE

9

§  Alzheimer’s Disease §  Broad spectrum of diseases, characterized by molecular markers specific to different paBent

populaBons

§  IdenBfy molecular markers to select paBents who will benefit from targeted AD therapies

TranslaBon of Precision Medicine Paradigm from Oncology to Alzheimer’s Disease

10

§  Cancer §  Broad spectrum of diseases, characterized by molecular markers specific to different tumors

§  Molecular test required for treatment decision

§  ~40% of new drugs have a companion diagnosBc

ANAVEX®2-73 Data IntegraBon and Data Analysis with KEM®

11

Population PK

DNA WES

RNA WES

Scores Baseline

MMSE ADCS-ADL

Scores Evolution

Delta MMSE Delta ADCS-ADL

Clinical assessment, Vital signs,

co-medication, …

WES: Whole Exome Genomic Sequencing

33311Genes

Rela3onLa6cegeneratedbyKEM®

Data Integration

Data Analysis

Helps idenBfy paBent selecBon clinical criteria

Helps idenBfy paBent selecBon biomarkers

Advanced Machine Learning Plaporm SupporBng Clinical Trial Design KEM® using Formal Concept Analysis (FCA) generates all

AssociaBon Rules:

>20 Million relaBons extracted and characterized from study data

UnbiasedsystemaKcanalysisidenKfieskeydriversofresponseatWeek57:

•  Concentra3onANAVEX®2-73•  SIGMAR1&COMTvariants

•  BaselineMMSE

ValidaBng Week 57 Drivers of Clinical Response at Week 148

FourkeydriversofresponseidenKfiedatWeek57withKEM®

SIGMAR1variant(n=5)

SIGMAR1wt

(n=15)

p=0.023p=0.030

1)Concentra3onAV2-73#(ng/mL)PartB

Low(n=9)

Medium(n=8)

High(n=9)

Improve

Worsening

ADCS-ADL

Delta

Week57

002 study1 003 study2

COMTvariant(n=4)

COMTwt

(n=16)

p=0.012

2)SIGMAR1-Q2Pvariant

3)COMT-Leu146variant

BSMMSELOW(n=8)

BSMMSEHIGH(n=13)

p=0.035

4)BaselineMMSE 12

# Plasma concentraBon of ANAVEX®2-73 is correlated with the administered dose

ValidaBng Week 57 Drivers of Clinical Response at Week 148

FourkeydriversofresponseidenKfiedatWeek57withKEM®

ResponsehypothesistestedatWeek148usingKEM®MMRM-LME

analysis

SIGMAR1variant(n=5)

SIGMAR1wt

(n=15)

p=0.023p=0.030

1)Concentra3onAV2-73#(ng/mL)PartB

Low(n=9)

Medium(n=8)

High(n=9)

Improve

Worsening

ADCS-ADL

Delta

Week57

COMTvariant(n=4)

COMTwt

(n=16)

p=0.012

2)SIGMAR1-Q2Pvariant

3)COMT-Leu146variant

BSMMSELOW(n=8)

BSMMSEHIGH(n=13)

p=0.035

4)BaselineMMSE 13

002 study1 003 study2

# Plasma concentraBon of ANAVEX®2-73 is correlated with the administered dose

Mixed Effect Models for Repeated Measures with Linear Time Effect (MMRM-LME) combined with Parameters extracted with KEM®

Mixed Effect Model for Repeated Measures¹ - Linear Mixed Effect2 :

§  Inter-paBent variability is modelled over Bme

§  Time is modelled as a conBnuous variable, hence reducing the number of parameters used in the adjustments² (Mixed Effect Model for Repeated Measures with Linear Bme effect -MMRM-LME)

§  Covariates included and tested in models:

−  KEM® idenBfied variables:

−  Other:

14

APOEε4Status categorical True;False

Age categorical Low;High

Sex categorical Female;Male

Donepeziltreatment categorical True;False

¹Lane,P.W.(2008).Handlingdrop-outinlongitudinalclinicaltrials:acomparisonoftheLOCFandMMRMapproaches.Pharmaceu3calSta3s3cs7:93–106²Verbeke,G.,Molenberghs,G.(2000).LinearMixedModelsforLongitudinalData.NewYork:Springer

VariableName Variabletype Categories

Concentra3on categorical Low/Med(<4ng/ml);High(≥4ng/ml)

BaselineMMSEscore categorical Low(<20);High(≥20)

SIGMAR1-Q2Pvariant categorical Absent;Present

COMT-L146FSvariant categorical Absent;Present

APOE ε4 Allele DistribuBon in ANAVEX®2-73 Study

15

à APOE ε4 carriers are 2.4 Bmes more frequent in the High AV2-73 concentraBon cohort compared to Low concentraBon cohort

à APOE ε3/ε2 carriers are 2.8 Bmes more frequent in the Low AV2-73 concentraBon cohort compared to High concentraBon cohort

High ANAVEX®2-73 concentraBon Cohort

Low ANAVEX®2-73 concentraBon Cohort

6 out of 8 paBents

75% APOE ε4 carriers in High AV2-73 concentraBon cohort

4 out of 13 paBents

30.7% APOE ε4 carriers in Low AV2-73 concentraBon cohort

PaBents treated with higher ANAVEX®2-73 ConcentraBon maintain ADCS-ADL1 Performance over the 148 Week Period, vs lower ConcentraBon cohort (p-value < 0.0001)

16

The covariates that are included in theMMRM-LMEmodel forADCS-ADLchangeare:3meascon3nuous,AV2-73concentra3ongroup(HighandLow/Med),sex,APOE ε4 status, age (Low, High), baseline MMSEscore, ongoing Donepezil treatment, SIGMAR1-Q2P,COMT-L146FSvariants,interac3onsbetween3meandconcentra3on group,3meandAPOEε4 status,3meand SIGMAR1, 3me and COMT, concentra3on groupand APOE ε4 status, and concentra3on group andSIGMAR1variant.

1Alzheimer’s Disease Co-operaBve Study – AcBviBes of Daily Living Inventory (ADCS-ADL)

In addiBon to ConcentraBon, the significant covariates idenBfied in MMRM-LME model are: SIGMAR1 (p<0.0080), COMT (p<0.0014) and APOE ε4 status (p<0.0001)

HighConcentraKoncohortshows88%differencetolowconcentraKoncohort

PaBents treated with higher ANAVEX®2-73 ConcentraBon show higher cogniBve MMSE1 Performance over 148 Weeks, compared to the lower ConcentraBon (p-value < 0.0008)

17

1Mini Mental State ExaminaBon (MMSE)

Covariates includedintheMMRM-LMEmodelforMMSE change are: 3me as con3nuous, AV2-73concentra3on group (High and Low/Med), APOEε4 status, age (Low,High), baselineMMSE score,SIGMAR1-Q2P variant, interac3ons between 3meand concentra3on group, 3me and APOE ε4status, 3me and SIGMAR1, and concentra3ongroupandSIGMAR1variant.

Other significant covariates idenBfied in MMRM-LME model are: APOE ε4 status (p<0.0001)

HighConcentraKoncohortshows64%lessdeclinethanlowconcentraKoncohort

SupporBng Precision Medicine Approach and Genomic Biomarker Hypothesis

SIGMAR1 / SIGMAR1-Q2P

Genomic biomarker idenBfied

using unbiased

systemaBc analysis of data rich

study

SIGMAR1 is confirmed target of

ANAVEX2-73

SIGMAR1 Crystal

Structure provides

consistent structural raBonale

SIGMAR1 RNA

expression data is

consistent

Biomarker hypothesis maintained

at week 148

Biomarker valid at mulBple

Bme points and mulBple end-points

18

Remarks regarding the ANAVEX®2-73-002/003 Studies

§  Data rich study (scores, PK, DNA, RNA) provides a unique opportunity to characterize response

§  CombinaBon of data rich study and KEM® unbiased systemaBc analysis enables idenBficaBon of biomarker hypothesis in a small paBent populaBon

§  Longitudinal study provides confirmaBon of biomarker effect idenBfied at week 57 at week 148

§  IdenBfied biomarker is consistent with a structural raBonale for the mechanism of acBon of ANAVEX®2-73 against its confirmed target SIGMAR1. The consistency of the DNA and RNA findings, as well as the longitudinal effect provides addiBonal strength to the iniBal biomarker-based hypothesis

19

Conclusions & PerspecBve §  The longitudinal 148-week data show that paBent cohort with the higher concentraBon of ANAVEX®2-73 maintains

the ADCS-ADL score and becer perform at MMSE, along the trial duraBon, when compared to the lower concentraBon cohort

§  A significant impact of SIGMAR1 and COMT biomarkers on the drug response level was confirmed over the 148-week period, irrespecBve of the fact that APOE ε4 carriers were more frequent in the higher concentraBon cohort

§  The hypothesis that ANAVEX®2-73 induces an improved clinical outcome with adequate effect size holds

§  Results demonstrate robustness by using both DNA- and RNA-based biomarkers, mulBple endpoints and Bme points. Excluding the paBents with the two idenBfied biomarker variants (approximately 20% of the populaBon), the resulBng 80% of the enrolled populaBon would lead to further clinically significant improved funcBonal and cogniBve scores

§  The combinaBon of KEM® FCA and MMRM-LME data analysis methodologies shows the innovaBve ability to idenBfy early biomarkers in clinical trials with small size-populaBon recruited

§  This study supports the study design of the iniBated ANAVEX®2-73 studies in several indicaBons underway, including a Phase 2b/3 study in 450 paBents with early Alzheimer’s disease

§  This approach may expand the access to Precision Medicine and Precision Pharmacology for a wide range of neurodegeneraBve diseases

20

Acknowledgments

Thanks to: §  Principal InvesBgators & clinical sites’ study staff

§  Data safety review commicee

§  Anavex SAB

§  Most of all, grateful acknowledgement of the contribuBon of the parBcipaBng AD paBents and their caregivers

ANAVEX is a trademark of Anavex Life Sciences Corp. 21

Contact Us

22

Corporate Office: Anavex®Life Sciences Corp. 51 West 52nd Street, 7th floor New York, NY 10019 1-844-689-3939

Shareholder & Media RelaBons: Core IR Scoc Gordon scocg@coreir.com www.anavex.com NASDAQ: AVXL

ANAVEX is a trademark of Anavex Life Sciences Corp.

Backup Slides

23

Plasma ConcentraBon of ANAVEX®2-73 is Correlated with the Administered Dose

24

Phase 2a Study Part A Total average drug exposure over Bme

AUC(0 to infinity) Area Under the Curve, 0-24h

ANAVEX2-73 Treatment

SIGMAR1Pro2variant(n=5)

SIGMAR1Gln2(n=15)

p=0.023

KEM® Analysis: Higher ANAVEX®2-73 ConcentraBon and Exclusion of SIGMAR1-Q2P Variant linked to Improved Response at Week 57

25

p=0.030

ConcentraBon ANAVEX2-73 (ng/mL) Part B

Low(n=9)

Medium(n=8)

High(n=9)

ADCS

-AD

L D

elta

from

Bas

elin

e (W

eek5

7)

SIGMAR1Q2Pvariant(n=5)

SIGMAR1Gln2(n=15)

p=0.023

Improve

Worsening

Results for change in ADCS-ADL scores at Week 57. Similar significant relaBonships were also found for change in MMSE scores.

Gene Markers and Baseline CharacterisBcs improve Effect Size (Cohen’s d) with ANAVEX®2-73

26

A higher Cohen’s d implies less paBents are needed to show a significant difference between placebo arm and ANAVEX®2-73 arm in a clinical study

ImprovementofScoresinWeek57fromBaseline

VeryLarge:1.20.0

Small:0.2

Medium:0.5

Large:0.8

VeryLarge:1.20.0

Small:0.2

Medium:0.5

Large:0.8

Excl. of SIGMAR1 Pro2 variant Excl. of COMT L146 variant MMSE baseline ≥ 20

All paBents (before marker pre-specificaBon)

Excl. of SIGMAR1 Pro2 variant MMSE baseline ≥ 20

ANAVEX®2-73 Phase 2b/3 Alzheimer's Disease Ongoing Study

N=450

Early AD paBent populaBon

•  Confirmed amyloid pathophysiology (CSF/amyloid PET)

•  PaBents aged 60 to 85

years •  MMSE score 20-28

•  DNA and RNA sequencing

Primary Endpoints at 48 Weeks •  ADAS-Cog •  ADCS-ADL •  Safety and tolerability of

ANAVEX®2-73

Key Secondary Endpoints •  CDR-SB •  Structural and funcBonal MRI •  Biomarkers: Abeta40/Abeta42, T-tau,

P-tau, NFL, YKL-40, neurogranin, BACE1

Pre-specified Endpoints •  GeneBc variants SIGMAR1

(rs1800866), COMT (rs113895332/rs61143203) with influence on treatment effect

ANAVEX®2-73 High dose#

ANAVEX®2-73 Medium dose#

Placebo

RandomizaBon 1:1:1

# Restricted to maintain complete blinding 27

CreaBng a Precision Medicine Franchise

ANAVEX®2-73

Novel target SIGMAR1

(homeostasis)

MulBple longitudinal end

Points (cogniBon:

MMSE, funcBon: ADCS-

ADL)

Extensive Genomics from NGS

(RNA, DNA)

MulBple potenBal

indicaBons

Longitudinal trial, extensive

PK/PD, IniBal safety established

Om

ic Plaporm

28