May 2018 Corporate Presenta2on

Christopher U Missling, PhD President & CEO

Nasdaq: AVXL

Safe Harbor

This presenta2on contains forward-looking statements made within the meaning of the Private Securi2es Li2ga2on Reform Act of 1995 by Anavex® Life Sciences Corp. and its representa2ves. These statements can be iden2fied by introductory words such as “expects,” “plans,” “intends,” “believes,” “will,” “es2mates,” “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 poten2al product applica2ons, poten2al collabora2ons, product development ac2vi2es, clinical studies, regulatory submissions and approvals, and similar opera2ng ma]ers. Many factors may cause actual results to differ from forward-looking statements, including inaccurate assump2ons and a broad variety of risks and uncertain2es, some of which are known and others of which are not. Known risks and uncertain2es include those iden2fied from 2me to 2me in reports filed by Anavex Life Sciences Corp. wit the Securi2es 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 obliga2on to update publicly any forward-looking statements, whether as a result of new informa2on, future events or otherwise. Anavex Life Sciences Corp. cannot be sure when or if it will be permi]ed by regulatory agencies to undertake clinical trials or to commence any par2cular phase of clinical trials. Because of this, statements regarding the expected 2ming of clinical trials cannot be regarded as actual predic2ons 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. Poten2al investors should refer to the risk factors in our reports filed on Edgar.

2

Novel Target, New Approach to Trea2ng CNS

Anavex u2lizes precision gene2c medicine to treat severe and

devasta2ng neurological disorders.

Anavex is focusing on rare diseases with no available therapy (Re]

syndrome) and high risk CNS pa2ent popula2ons (Alzheimer’s disease,

Parkinson’s disease) 3

Summary

4

ANAVEX®2-73, orally available S1R agonist with strong IP (COM 2033) and has completed a successful Phase 2a clinical trial for Alzheimer’s disease U2lizing pa2ent genomic analysis as well as clinical PK/PD data to effec2vely incorporate into three clinical trials ini2a2ng in 2018:

§  Phase 2 clinical trial in Re] syndrome* – IND filed §  Phase 2 clinical trial in Parkinson’s disease demen2a §  Phase 2/3 clinical trial in Alzheimer’s disease

*FDA granted ANAVEX®2-73 Orphan Drug Designa<on (ODD) for ReB syndrome

Focus Finding effec2ve treatments for neurodevelopmental and neurodegenera2ve diseases, areas of high unmet need

Mechanism Sigma-1 Receptor (S1R) targe2ng cellular homeostasis

Approach Applying precision medicine to CNS

Iden2fica2on of Gene “Signature” from ANAVEX®2-73 Pa2ents

ANAVEX®2-73 Phase 2a clinical trial

5

ANAVEX®2-73 treatment

NOW: Gene2c signatures of the strongest responders to ANAVEX®2-73

Corresponding approach to

oncology precision medicine

Pornolio of Compounds Varying in Sigma-1 Receptor Binding Ac2vi2es

6

PRECLINICAL PHASE 1 PHASE 2 PHASE 3

ANAVEX®2-73 *RETT SYNDROME

ALZHEIMER’S DISEASE

PARKINSON’S DISEASE

FRAGILE X

CANDIDATE

ANAVEX®3-71 (AF710B)

*FRONT. DEMENTIA (FTD)

ALZHEIMER’S DISEASE

PARKINSON’S DISEASE

ANAVEX®1-41 DEPRESSION

STROKE

PARKINSON’S DISEASE

ALZHEIMER’S DISEASE

ANGELMAN’S

ANAVEX®1066

CANCER (PANCREAS)

ACUTE & NEUROPATHIC PAIN

* = Orphan Drug Designa<on by FDA

*INFANTILE SPASMS

VISCERAL PAIN

ANAVEX®2-73 is a S1R Agonist and Ac2vates the Sigma-1 Receptor

7

Enhancing ac2va2on of endogenous S1R agonist with ANAVEX®2-73 remedies

disease symptoms and underlying pathophysiology

1) Mavlyutov TA et al. Neuroscience. 2013 Jun 14;240:129-34 2) Su TP et al. Trends Pharmacol Sci. 2016 Apr;37(4):262-78 3) Ruscher K et al. J Pharmacol Sci. 2015 Jan;127(1):30-5

S1R is an integral membrane protein involved in cellular homeostasis which

targets restora2on of neuroplas2city and cellular stress response2,3

S1R deficiency accelerates

disease progression1

Endogenous S1R agonists ac2vate the Sigma-1 Receptor in situa2on

of cellular stress

Sigma-1R Agonists MoA: Restoring Homeostasis

ANAVEX®2-73

Source: Adapted from Miki et al, Dec 9. doi: 10.1111/neup.12080 Neuropathology 2013 Glembotski et al., Circula<on Research. 2007;101:975-984

Restoring Homeostasis

Villard et al., J. Psychopharmacol. 2011

Su et al., Trends Pharmacol Sci. 2016

Sigma-1R helping / s2mula2ng own body to regain func2onality

[σ1 Antagonist]

8

9

Endoplasmic Re2culum (ER) -Mitochondrial Axis Membrane (MAM) is Key Area Involved in Neurodegenera2ve Diseases

Common Cellular Processes in Neurodegenera2ve Diseases

P. Gómez-Suaga Cell Death Dis. 2018 Mar; 9(3): 337.

Milleretal.TrendsNeurosci.,2016;Lahmyetal.Neuropsychopharmacol.,2013

Normal condi2on

Sigma-1 Receptor Restores MAM Associa2on

S1R

ANAVEX®2-73

Disease condi2on

•  Normally quiescent, S1Rs become ac2vated during periods of cellular stress

•  ANAVEX®2-73 is well-posi2oned to enhance this response

10

Sigma-1R Translocates to Play a Role in Gene Transcrip2on: Func2onal Connec2on Between Cell Body and DNA

Upon Ac2va2on, the S1R is relocated to the nuclear envelope (NE), where it is involved in controlling gene transcrip2on

11

Mouse re2nal ganglion cell illuminated by Thy-1 driven GFP; immunostaining of S1R in red. Scale = 50 μm

Sigma-1R Ac2ve in the Cell Body

Rat dorsal root ganglia; arrows indicate S1R detected in nuclear envelope and ER. Scale = 2 μm

Sigma-1R located at the ER and NE

The Sigma-1R is mainly expressed in the cell body at the MAM

Yang et al., Neuroscience 331: 148–157, 2016; Guo et al., Sci Rep. 5:10689, 2015 Tsai et al. Proc Natl Acad Sci U S A. 112(47): E6562–E6570, 2015

Overview ANAVEX®2-73 Clinical Trials

ANAVEX®2-73-001 Study: •  Randomized, double-blind, placebo-

controlled Phase 1 (oral) •  Single ascending dose (SAD) •  22 healthy subjects

Popula2on PK, i.e. non-linear mixed effect (NLME) modeling, non-compartmental analysis and formal concept analysis (FCA) and both RNA and whole exome DNA genome sequencing using Illumina HiSeq 2500 Next Genera2on Sequencing (NGS) technology

ANAVEX®2-73-002 Study#: •  Randomized, Phase 2a (iv/oral) •  32 mild-to-moderate AD pa2ents •  MMSE baseline 16-28 (mean 21) •  Adap2ve trial with Popula2on PK •  Bioavailability, dose finding (PART A), and

exploratory efficacy with 52 week open-label extension (PART B)

Prepara2on underway

Ini2a2on of subsequent randomized, double-blind, placebo-controlled ANAVEX®2-73 studies: •  Re] syndrome •  Parkinson’s disease demen2a •  Alzheimer’s disease

ClinicalTrials.gov Iden<fier: #NCT02244541; ##NCT02756858

ANAVEX®2-73-003 Study##: •  208-week extension study awer PART B

12

Using Precision Medicine to Increase Clinical Trial Success Rate

13ThomasDWetal.ClinicalDevelopmentSuccessRates2006-2015.BIOIndustryAnalysis

+64%

+38%

14

Re] Syndrome (RTT): A Devasta2ng Monogenic Disorder

§  Re] syndrome (RTT) is caused by spontaneous (de novo) muta2on in the MECP2 gene located on the X chromosome

§  For males the gene muta2on is lethal since males have only one X chromosome (females have two X chromosomes)

§  Affects approximately 16,000 females in U.S. §  1:10-15K females worldwide

§  For females who survive infancy, RTT leads to a deficiency in motor func2on, cogni2ve impairment and seizures

§  There are no approved treatments for RTT

§  FDA granted ANAVEX®2-73 Orphan Drug Designa2on for Re] syndrome

Rare gene2c postnatal progressive neurodevelopmental disorder

Maria Chahrour, Huda Zoghbi., The Story of ReB Syndrome: From Clinic to Neurobiology, Science Direct (2007); D.Valen< et al., Neuroscience and Biobehavioral Reviews 46 (2014) 202–217

BDNF X MECP2 gene

15

MECP2 is Mutated in Re] Syndrome Leading to Loss of Neuronal Func2on and Loss of BDNF

15

§  MECP2 is a calcium dependent gene, affects dendri2c spine development and necessary for other gene expressions, including BDNF

§  Loss of MECP2 func2on alters excitatory/inhibitory synap2c balance §  MECP2 func2on required for neuronal survival, synap2c development and plas2city §  BDNF is an important neuronal plas2city-related gene affected by loss of MECP2

Fasolino M et al., The Crucial Role of DNA Methyla<on and MeCP2 in Neuronal Func<on. Grayson DR, ed. Genes. 2017;8(5):141; Benarroch EE, Neurology. 2015 Apr 21;84(16):1693-704.; Greer PL et al., Neuron. 2008 Sep 25;59(6):846-60

Healthy Individual

MECP2 gene BDNF

Re] Syndrome Individual

X X

Beneficial effect of ANAVEX®2-73: Restores calcium homeostasis

ANAVEX®2-73

ANAVEX®2-73 Regulates Gene Expression and Restores BDNF Levels

16Presented at An<epilep<c Drug Trials XIV 2017 Conference

ANAVEX®2-73 fully restores BDNF expression levels in the hippocampus in the Fmr1 KO mouse model (p<0.05, KO vehicle vs. KO ANAVEX®2-73)

p<0.05

ANAVEX®2-73 Significantly Reduces Impairment in Mutated MECP2 Re] Syndrome Mouse Model

0

10

20

30

40

50

60

70

80

90

100

Clasping

Hindlim

bs(%

)

Mecp2_WTVehicle Mecp2_HETVehicle

Mecp2_HETAV2-73(10mg/kg) Mecp2_HETAV2-73(30mg/kg)

***

*

0

10

20

30

40

50

60

70

80

90

100

Clasping

Hindlim

bs(%

)

Mecp2_WTVehicle Mecp2_HETVehicle

Mecp2_HETAV2-73(10mg/kg) Mecp2_HETAV2-73(30mg/kg)

**

*

Clasping at 8 weeks

Clasping at 12 weeks

p<0.001

p<0.05

p<0.05

p<0.01

Normal Impaired

Mice treated with ANAVEX 2-73 (30 mg/kg) clasped less than vehicle-treated mutant mice (p<0.05 at 8 and 12 weeks)

17

Presentedat2016EpilepsyPipelineConference,2016ReMSyndromeSymposium

Significant Improvement in Mul2ple Movement Impairments

18

Motor Coordina2on and exercise capacity are assessed: ANAVEX®2-73 treated mice took significantly more 2me to fall off rod & fell at higher speeds compared to vehicle-treated mutant mice

Rotarod Planorm that employs computer vision to detect changes in gait geometry and gait dynamics: Gait, Correla2on, Body Mo2on demonstrate significant improvement

Neurocube Wild type (WT) mice have a higher startle response compared to impaired mice: ANAVEX®2-73 treated mice showed a significant increase in startle response compared to vehicle-treated mutant mice

Startle

Presentedat2016EpilepsyPipelineConference,2016ReMSyndromeSymposium

ANAVEX®2-73 Phase 2 Re] Syndrome Study Design

19

Randomized, Double-Blind, Placebo-Controlled Study of ANAVEX®2-73

4 weeks Baseline

Observa2on

N<90

8 weeks Full Dose

Treatment

12 Weeks Voluntary

Open Label

Titra2on Treatment

Period

Baseline Observa2on Period

Full Treatment

Period

4 weeks Dose Titra2on

Randomiza2on to 1 of 3 arms

Ini2al screen

AV 2-73: High dose

Placebo

AV 2-73: Low dose

AV 2-73: High dose

Placebo

AV 2-73: Low dose

20

Parkinson’s Disease Demen2a (PDD): A Devasta2ng Demen2a Disorder

§  Parkinson's disease is a fairly common neurological disorder in older adults, es2mated to affect nearly 2 percent of those older than age 65

§  About 1 million Americans have Parkinson's disease

§  It is es2mated that 50 to 80 percent of those with Parkinson's disease eventually experience Parkinson's disease demen2a

§  The brain changes caused by Parkinson's disease begin in a region that plays a key role in movement

§  As Parkinson's brain changes gradually spread, they owen begin to affect mental func2ons, including memory and the ability to pay a]en2on, make sound judgments and plan the steps needed to complete a task

Parkinson’s disease demen2a: Demen2a occurs a year or more awer the onset of motor symptoms

www.alz.org/demen<a/parkinsons-disease-symptoms

ANAVEX®2-73 Targets MAM to Reduce Cellular Damage: How it May Work in Parkinson’s Pathogenesis

21

ANAVEX2-73

§  A specific type of phosphorylated α-syn aggregate leads to neurotoxicity in PD

§  These aggregates co-localize with MAM

§  They induce mitochondrial toxicity, oxida2ve and energe2c stress, mitochondrial fragmenta2on and mitophagy

Grassi et al., PNAS March 13, 2018. 115 (11) E2634-E2643

MAM: Mitochondria-Associated Membrane

Beneficial effect of ANAVEX2-73

Parkinson’s Disease Model: ANAVEX®2-73 Significantly Improves Motor Behaviors

22

§  ANAVEX®2-73 was evaluated in the 6-OHDA Parkinson’s disease model

§  ANAVEX®2-73 significantly improves motor behaviors compare to a double-blind control group (saline)

§  (A) Spontaneous rota2on ac2vity §  (B) Cylinder test of forelimb use asymmetry

§  (C) Stepping test of forelimb use asymmetry

Cenci et al., presented at World Parkinson Congress 2016

ANAVEX®2-73 Normalizes Pathophysiological Biomarkers

23

ANAVEX®2-73 significantly decreased the expression of CD68 (marker of ac2vated microglia) in the substan2a nigra

Cenci et al., presented at World Parkinson Congress 2016

Tyrosine-hydroxylase fibers

ANAVEX®2-73 significantly increases tyrosine-hydroxylase fibers (marker of dopaminergic neurons) in the striatum

These results support the hypothesis that pharmacological s2mula2on of the sigma-1 receptor may have both disease-modifying and symptoma2c effects in Parkinson’s disease

ANAVEX®2-73 reduces microglia over-ac2va2on ANAVEX®2-73 restores dopaminergic neurons

52 weeks 104 weeks

ANAVEX®2-73-003 Alzheimer’s Disease Study: Con2nued Favorable Safety and Tolerability through 109 weeks

1.  Es2mate the maximal tolerated dose (MTD)

2.  Explore a dose-effect rela2onship 3.  Es2mate the bioavailability of

ANAVEX 2-73

52 weeks

0 12 days 36 days

wash out period

0 5 weeks

1st Period

2nd Period

PART A 002 Study#

1.  Establish con2nued safety and tolerability of ANAVEX 2-73

2.  Explore a dose-effect rela2onship

PART B 002 Study#

57 weeks 109 weeks

Establish con2nued safety and tolerability of ANAVEX 2-73

003 Study##

ClinicalTrials.gov Iden<fier: #NCT02244541; ##NCT02756858

52 weeks

24

Part B: All pa2ents on ANAVEX®2-73 oral daily doses of 10mg, 20mg, 30mg, 50mg according to pre-specified

adap2ve trial design implemented during Part A

ANAVEX®2-73 Primary and Secondary Endpoints Met in Phase 2a Clinical Trial of Mild-to-Moderate Alzheimer’s Pa2ents

§  Phase 2a results demonstrate a favorable safety, bioavailability, dose-response curve and tolerability/risk profile at doses between 10mg and 50mg of oral daily ANAVEX®2-73

§  Primary endpoints met with favorable safety and tolerability

§  Secondary endpoints met with suppor2ve exploratory biomarker, cogni2on and func2on measures correla2ng

§  Dose-response rela2onship was sta2s2cally significant to affect MMSE-Δ and EEG/ERP-Δ scores with MMSE-Δ (p=0.0285) and EEG/ERP-Δ (p=0.0168), respec2vely

25Macfarlane, presented at CTAD 2016

ANAVEX®2-73 Primary Endpoint Safety Data measured to 57 weeks:

26

§  The most common adverse event (AE): mild dizziness

§  When pa2ents were first dosed with highest dose

§  Was transient and reversible

§  Consistent with Blood Brain Barrier (BBB) penetra2on

§  98% of all AEs were mild or moderate and reversible with 76% being Grade 1

§  2% were not drug-related Grade 3

§  There were no Grade 4 and 5 events

§  AE profile similar to that of healthy volunteer Phase 1 data

§  No differences in blood pressure or res2ng heart rate

§  Clinical laboratory parameters, vital signs, and 12-lead ECG did not show any clinically relevant or dose-dependent changes

Voges et al., presented at CNS Summit 2014; Macfarlane, presented at CTAD 2016

Secondary Endpoints: High ANAVEX®2-73 Concentra2on linked to Consistent Improved Response Across All Analytes and Periods

27

ANAVEX®2-73 concentra2on

MMSE Improvement

Part A1 [0-24h] Immediate response

Part A2 [24-264h] Short-term response

Part B [52 weeks] Long-term response

Implies

ADCS-ADL Improvement

Part A1 [0-24h] Part A2 [24-264h] Part B [52 weeks] Immediate response Short-term response Long-term response

ANAVEX®2-73 shows a consistent response across the 3 different 2mes frames:

Afshar et al., presented at CTAD 2017

Robust Dose(Concentra2on)/Response Effect of ANAVEX®2-73

28

54% High dose -> Improved

response

43% Low dose -> Poor response

High dose -> Poor response or Low dose -> Improved response

3%

97%

97% Consistency: MMSE, ADCS-ADL and EEG/ERPs: Iden2fied rela2ons show that high dose (concentra2on) is linked to improved

response and low dose (concentra2on) to poor response

Systema2c explora2on of the full data matrix using KEM® demonstrates consistent concentra2on-response rela2onship for 6 main exploratory endpoints: cogni2on, func2on and biomarker (MMSE, ADCS-ADL, EEG/ERPs)

Afshar et al., presented at CTAD 2017

29

Increasing

Decreasing

High Medium Low

Concentra2on ANAVEX2-73 (ng/mL), Part B

Rela2on between ANAVEX®2-73 Concentra2on and MMSE An increase of MMSE during 57 weeks is a rare event. A pa2ent receiving a higher

concentra2on of ANAVEX2-73 has a 2.1-fold chance of improving its MMSE

MMSE increases High Concentra2on

Low Concentra2on

MMSE decreases

Afshar et al., presented at CTAD 2017

Rela2on between ANAVEX®2-73 Concentra2on and ADCS-ADL

30

An increase of ADCS-ADL during 57 weeks is a rare event. A pa2ent receiving a higher concentra2on of ANAVEX2-73 has a 1.6-fold chance of improving its ADCS-ADL

Concentra2on ANAVEX2-73 (ng/mL), Part B

High

Medium

High Medium Low

ADCS-ADL increases

ADCS-ADL decreases

High Concentra2on

Low Concentra2on

Low

Afshar et al., presented at CTAD 2017

Pa2ent Cohort with Cogni2ve and Func2onal Improvements at 57 Weeks: Retained Response at 109 Weeks

10 12 14 16 18 20 22 24 26 28 30

0 5 17 31 41 53 57 70 83 96 109

MM

SE

Weeks

101009

101011

101013

101014

102006

102010

30 35 40 45 50 55 60 65 70 75 80

0 5 17 31 41 53 57 70 83 96 109

AD

CS-

AD

L

Weeks

101009

101011

101013

101014

102006

102010

MMSE and ADCS-ADL remained steady over 27 months (109 weeks)

§  Cohort displayed highest concentra2ons of ANAVEX®2-73

31

§  Pa2ents with milder disease stage (baseline MMSE >20) tended to respond be]er to ANAVEX®2-73 than pa2ents with more advanced disease stage (baseline MMSE <20)

Afshar et al., presented at CTAD 2017

MMSE Δ and ADCS-ADL Δ Significantly Different to SoC AD

32

§  Comparison to historical control subjects with mild-to-moderate AD with comparable MMSE baseline, assigned to the placebo arm from pooled cohort study conducted by the Alzheimer Disease Coopera2ve Study Group, age adjusted#

C Bernick, J Cummings, R Raman, X Sun, P Aisen, Arch Neurol. 2012;69(7):901-905. doi:10.1001/archneurol.2011.3758. RG Thomas, M Albert, RC Petersen, PS Aisen, Alzheimers Dement. 2016 May;12(5):598-603; Data: Macfarlane, presented at CTAD 2016

1.8 MMSE points improvement to historical control (SoC)# at week 57 (p=0.0164)

4 ADCS-ADL points improvement to historical control (SoC)# at week 57 (p=0.0186)

1.8 MMSE points difference 4 ADCS-ADL points difference

Summary

§  ANAVEX®2-73 appears to have a favorable safety profile and to be generally well tolerated

§  ANAVEX®2-73 has demonstrated efficacy in the clinic as well as in mul2ple preclinical disease models valida2ng the Sigma-1R mechanism of ac2on

§  Gene2c Signatures for those who respond best to ANAVEX®2-73 have been determined

§  These signatures can be applied to neurological indica2ons beyond Alzheimer’s disease, such as Re] syndrome and Parkinson’s disease demen2a

§  Three clinical trials will be ini2ated in 2018 for Re] syndrome, Alzheimer’s disease and Parkinson’s disease demen2a

§  Anavex has enough cash for 2 years

33

Financial Posi2on and Near Term Catalysts

34

§  Cash (as of March 31, 2018): $25.7M; No debt

§  The company is well capitalized to achieve clinical readouts

Orphan Drug Designa2ons granted for the following indica2ons: Re] syndrome, Infan2le spasms and Frontotemporal demen2a

Phase 2a – Reported 109 week data at CTAD scien2fic mee2ng

Phase 2a – PK/PD data CTAD scien2fic mee2ng

Phase 2 clinical trial in Re] syndrome – IND filed

Phase 2 clinical trial in Parkinson’s disease demen2a (PDD)

Phase 2/3 clinical trial in Alzheimer’s disease

Ongoing in-licensing/out-licensing review to op<mize value of pipeline

þ

þ þ

Anavex Life Sciences Exper2se

35

ChristopherU.Missling,PhD

President&CEO

FDA Commissioner's Award of Excellence

ManagementTeam

EmmanuelOFadiran,RPh,PhD

SVPofRegulatoryAffairs

PaulVancutsem,DVM,PhD

VPofPreclinicalDevelopment

Jeffrey Cummings, MD

Paul Aisen, MD

Harald Hampel, MD, PhD

Norman Relkin, MD, PhD

Abraham Fisher, PhD

ScienIficAdvisoryBoardMembers

StephanToutain,MS,MBA

SVPofOperaIons

DanielKlamer,PhD

VPofBusinessDevelopment&ScienIficStrategy

Jacqueline French, MD

Andrew Cole, MD

Tanya Simuni, MD

Daniel Weintraub, MD

Tangui Maurice, PhD

Contact Us

36

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

Shareholder & Media Rela2ons: Solebury Trout mpurcell@soleburytrout.com www.anavex.com NASDAQ: AVXL

ANAVEX is a trademark of Anavex Life Sciences Corp.

Back Up Slides

37

Comprehensive Phase 2a Pa2ent Characteriza2on to Iden2fy Ac2onable Phase 2/3 Clinical Trial Parameters

38

Ariana’s KEM® data analy2cs: §  Systema2c integrated analysis of all

combined parameters §  Iden2fica2on of ac2onable parameters §  Design of an op2mized Phase 2/3 clinical trial

Popula2on PK

DNA FGS

RNA FGS

Scores Baseline

MMSE ADCS-ADL COGSTATE EEG/ERP HAM-D

Scores Evolu<on

MMSE ADCS-ADL COGSTATE EEG/ERP HAM-D

Clinical assessment, Vital signs,

co-medica<on, …

==

FGS: Full Exome Genomic Sequencing

Gut Microbiota

Example of a Gene “Signature”: BDNF Polymorphism Val66met

Sources: 1) Zeev BB et al Neurology. 2009 Apr 7;72(14):1242-7 2) Boots EA et al Neurology. 2017 May 3; 3) Tanila H Neurobiol Dis. 2017 Jan;97(Pt B):114-118

BDNF Val66met polymorphism directly correlates with:

AcceleratedcogniIvedeclineandincreasedAβaccumulaIon

inAlzheimer’sdisease2,3

BDNF Val66met Polymorphism implicated in Neurodevelopmental and Neurodegenera2ve Disorders

HigherseizurefrequencyandseverityofReVsyndromesymptoms1

39

1/3 of all pa2ents have this muta2on

Example of a Targeted Genomic-Driven Clinical Trial Approach in Alzheimer’s Disease

40BootsEAetal.,Neurology.2017May30;88(22):2098-210BrookmeyeraRetal.,Alzheimer’s&DemenYa.2017inpress

Pa2ent Genomic Analysis - Number of Associated Gene2c Muta2ons Linked to Alzheimer’s Disease have Increased

41E.Cuwersetal.,LancetNeurol.2016Jul;15(8):857-868

GWAS = genome-wide associa2on studies

Contribu2on of gene variants to the development of Alzheimer's disease has clinical implica2ons, including enhancing diagnos2c accuracy and providing targets for pre-specified drug development

Rare Disease Drug Discovery Approach: Higher Success Rate of Clinical Trials Expected

42

Shiw to Use Precision Medicine to Break the No2on That Alzheimer’s is a Single Disease §  Researchers are star2ng to combine gene2cs with lessons learned from the

failed β amyloid-based clinical trials, not only to find new targets but also to stra2fy pa2ents

§  The view now is that the disease is more like cancer, a heterogeneous condi2on that can be kicked off by a variety of cellular mechanisms

§  The key is to iden2fy those mechanisms and match them to the right pa2ents

43

Alzheimer’s disease research has moved away from β amyloid, tau, and cholinergic targets and shiwed toward other targets

Breakdown of the alterna2ve targets in 2017

McCallister, E. “Diagnosing AD trials.” BioCentury (2017)

Examples of Con2nued Improvements and Reported Events ‘Therapeu2c Response’ during 57 Weeks

44

PATIENT EVENTS:THERAPEUTICRESPONSEUNEXPECTED

101001 MOREALERTREGARDINGSURROUNDINGS

101002 FEELSMUCHHAPPIERMAKINGJOKES

101003 MUCHHAPPIERWHENATTENDINGCLINICAPPTSANDENJOYSMAKINGJOKESANDENGAGESWELLINCONVERSATION

101004 BETTERHANDCOORDINATION.CALMERANDMORECOMMUNICATIVE

101006 IMPROVINGMOODS.READINGMOREBOOKS

101007ABILITYTOPLAYTHEPIANOANDREADMUSICNOTESATABOUT9MONTHSINTOTRIAL.SHEUSEDTOPLAYTHEPIANOATAGE5ANDLOSTHERABILITYPRE-ALZHEIMERTRIAL

101010 ABLETOFOLLOWPLOTWHENWATCHINGMOVIESWHEREASPREVIOUSLYCOULDNOT

101010 MORECOMPASSIONFORCHILDREN

101011 WIFETHINKSPATIENTISABITMORECHEERFUL

101013 ABLETODOMUCHMOREHOUSEWORKTHANBEFORE

101013 MOREDRIVENANDUPBEATLESSANXIOUSACCORDINGTOCARER

101014ANINTERNATIONALARTISTWHORESUMEDHERPAINTINGABILITIESANDNOWHAVINGANEXHIBITIONINNOV2016.WRITTENA3PAGELETTERTOLONGLOSTBROTHER

101015 PLAYINGMOREGOLFNOWBYHIMSELF.MORECONFIDENTATGOINGOUTBYHIMSELF

101017 ENJOYEDHERTRIPTOBELGIUM-TALKSABOUTSOMEBITSOFHERTRIP

102001 IMPROVEDENGAGEMENTWITHFAMILY/FRIENDS/OUTSIDEWORLD

102008 IMPROVEMENTINMOOD

102010 FEELINGGREAT-IMPROVEMENTINCOGNITIONANDMOOD,BALANCEANDGAITHASIMPROVED

103001 PATIENTREMEMBERINGSOMETHINGHEWOULDN'THAVEPREVIOUSLY

10

12

14

16

18

20

22

24

26

28

30

0 10 20 30 40 50 60

MM

SE

Weeks

Examples of MMSE "Strong" Pa2ent Responders

HAM-D: Reduc2on of Insomnia, Anxiety and other Symptoms

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

Insomnia 8 29%

Work and ac2vi2es 6 21%

Anxiety (psychic and soma2c) 5 18%

Agita2on 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

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Baseline 31 week

HAM

-D M

ean

± SE

M

*p<0.05

45

ANAVEX®2-73: Robust Correla2on of Cogni2on, Func2on and Behavior Response

46

§  Principal component analysis of the Δ sub-scores between week 31 and baseline for MMSE (MM), ADCS-ADL (AD), and HAM-D (HA)

Good = increasing MM& AD, decreasing HA Bad = decreasing (MM & AD), increasing HA

ANAVEX®2-73 Response cluster in a homogenous manner: Consistent response across mul2ple domains

ANAVEX®2-73 Rescues Synap2c Networks and has Posi2ve Effect on Cogni2on and Behavior

EEG/ERP peak measures (P300)

ERP target detec2on task measures

Cogstate: Cogni2ve measures

MMSE: Cogni2ve measures

ADCS-ADL: Behavioral measures

1.  ERP peak measures (P300): fundamental measures of synap2c network performance

2.  ERP target detec2on task measures: direct measures of a]en2on, speed of brain processing, and simple behavioral performance

3.  Psychometric measures (Cogstate) cogni2ve measures: Detec2on: processing speed (psychomotor func2on), Iden2fica2on: reac2on 2me (a]en2on), One Back: working memory (cogni2on), One Card Learning: visual learning (visual memory), ISLT: verbal learning, ISLT-delay: verbal memory

4.  Psychometric measures (MMSE): cogni2ve measures

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

Each of these metrics measures a higher level of brain func2on

47

Comprehensive Pre-Specified PK Sampling Protocol during Phase 2a Study

48

Measures(hours)

48 120 192 264

012 6 8 12 18 24

72 48 120 192 264

012 6 8 12 18 24

72

Dailyintake

Period1 Washout Period2

PartA:IV(3/5mg),Oral(30/50mg) PartB:Oral(10to50mg)

Part B: All pa2ents on ANAVEX®2-73 oral daily doses of 10mg, 20mg, 30mg, 50mg according to pre-specified adap2ve trial design implemented during Part A

Clearance of ANAVEX®2-73 Independent of given Dose

49

Total average drug exposure over 2me AUC(0 to infinity)

Area Under the Curve, 0-24h

ANAVEX2-73 Treatment

Confirmed Reliable Inter-Individual Variability (Dispersion) for the ANAVEX2-73 Phase 2a Study with 32 Pa2ent Cohort

50

§  Evalua2on of the dispersion index of all the 32 pa2ent of the Phase 2a reveals that above any random sample of 16 pa2ents, the dispersion index is maintained at a fixed level with the narrowest confidence intervals

§  That is confirma2on that the sample of 32 pa2ents of the Phase 2a provides reliable informa2on regarding dispersion and as such allows for meaningful predic2ons for larger popula2ons

12 14 16 18 20 22 24 26 28 30 32-13

-12.5

-12

-11.5

-11

-10.5

-10

-9.5

-9

-8.5

-8

Sample size

Disp

ersi

on in

dex

Real data

12 16 24 32

-20

-18

-16

-14

-12

-10

-8

Disp

ersi

on in

dex

Sample size

Bootstraped data

Alzheimer Disease Progression: Comparable cogni2ve decline in open-label studies as in placebo-controlled studies

51

Progressive decline in cogni2on: Open-label study with SoC#

# Doody RS et al (2001) Arch Neurol. 58(3):427-433 (SoC = donepezil) ## Figure adapted from Doody RS et al (2013) N Engl J Med; 369:341-350 (SoC = Ach inhibitors and/or meman<ne)

Progressive decline in cogni2on: Double-blind placebo-controlled study with SoC##

Placebo(Donepezil)Donepezil5mg(Donepezil)Donepezil10mg(Donepezil)

52 weeks

52 weeks

Weeks

52 0 12 28 40 64 76

ADAS

-Cog

Cha

nge

from

bas

elin

e

§  Open-label and double-blind controlled studies equivalent for long-term cogni2on changes

ANAVEX®2-73: Dose-Dependent An2-Seizure Effects

52

0

10

20

30

40

50

60

70

80

90

100

MES-induced convulsions

PTZ-induced convulsions

% o

f Sei

zure

redu

c2on

PresentedatAESMeeYng2015,#resultshavebeenconfirmedbytheETSPscreeningprogram;PresentedatAEDD2017

Significant Seizure Reduc2on with ANAVEX®2-73 in both MES and PTZ-Induced Seizure Models

Vehicle 10 mg/kg (p.o.)

30 mg/kg (p.o.)

100 mg/kg (p.o.)

p=0.0065

Significant Seizure Reduc2on with ANAVEX®2-73 in Angelman Seizure Model ANAVEX 2-73 (10 mg/kg ip dosed daily for 14 days)

p<0.001

Significant Reduc2on Number of Spasms with Pre-treated ANAVEX®2-73 in Infant Rat Model

(30mg/kg ip)�

ü  At all doses tested ANAVEX®2-73 reduced novelty/stress-induced ac2vity while basal ac2vity levels were not significantly affected

ü  Mouse behavioral and motor pa]erns were completely normal; no signs of dystonia or stereotypic behaviors were observed

ü  Chronic treatment with ANAVEX®2-73 (0.3 & 1.0 mg/kg) to 6-OH-DA-lesioned mice yielded a general motor recovery, accompanied by improved dopamine neuronal survival, and reduced microglia ac2va2on in the substan2a nigra

These results support the hypothesis that pharmacological s2mula2on of the S1R may have disease-modifying effects in

parkinsonian disorders, and iden2fy ANAVEX®2-73 as a suitable inves2ga2onal drug for these indica2ons

Posi2ve Preclinical Data in Parkinson’s Disease

Cenci et al., presented at World Parkinson Congress 2016 53

Sigma-1 Receptor Ac2va2on and Neurodegenera2ve Diseases

54

Novel Target: Sigma-1 Receptor

55Su et al., Trends Pharmacol Sci. 2016

Confirmed Effects of Sigma-1 Receptor Ac2va2on …

ü  Synaptogenesis

ü  Restores Ca2+ imbalance

ü  Reduces Inflamma2on

ü  Reduces Oxida2ve stress

ü  Reduces Tau hyper-phosporyla2on

ü  Restores Mitochondrial dysfuncion

ü  Reduces Protein Misfolding

56

… effects relevant in both neurodevelopmental as well as neurodegenera2ve diseases

ANAVEX®3-71 Significantly Decreases Hallmark Pathologies in 3xTg-Alzheimer’s Disease Model

§  10 month-old 3xTg-AD and WT mice

§  administered i.p. with tap water or ANAVEX®3-71 (10 mcg/kg/day) for 2 months

Source: Fisher et al., Neurodegenera<ve Diseases 2015 DOI: 10.1159/000440864 57

Sigma-1 Receptor’s Role in Regula2ng Gene Transcrip2on

58

Sigma-1 receptor agonist such as ANAVEX 2-73

Adapted from Su, Tsai et al.,Proc Natl Acad Sci USA 2015 Nov 24; 112(47):E6562-E65570

S1R can translocate to the nuclear envelope where it binds emerin that in turn recruits barrier-to-autointegra2on factor (BAF) and histone deacetylase (HDAC) to form a complex with specific protein 3 (Sp3) which can then suppress the gene transcrip2on of monoamine oxidase B (MAOB)

Pathological GSK-3β Ac2va2on can be Inhibited with ANAVEX®2-73

Source: Inestrosa et al. Journal of Molecular Cell Biology (2014), 6, 64–74

Injec2on of Aβ25-35 yields a hyper-inflammatory state that is accompanied by increases in GSK-3β phosphoryla2on in the hippocampus --> An Effect reduced by ANAVEX 2-73

Possible means to impact underlying pathology of various neurodegenera2ve and neurodevelopmental disorders

Lahmy et al., Neuropsychopharmacol., 2013

Ac2ve GSK-3β has been found in AD brains with neurofibrillary changes and an increase in tau hyperphosphoryla2on, neurodegenera2on and spa2al learning deficits. Ac2vated GSK-3β also s2mulates the amyloidogenic processing of amyloid precursor protein (APP) by β- and γ-secretases

59

60 Sources: GlobalGenes.org1, PhRMA, NIBR 60

61