anavex®‐7 as a potential treatment for...anavex®‐7 as a potential treatment for rett syndrome...

ANAVEX®2‐73 as a Potential Treatment for Rett Syndrome and other Pediatric

or Infantile Disorders with Seizure Pathology

Christopher U Missling, PhD, President & CEO

ASENT ConferenceMarch 2018

Safe Harbor

This presentation contains forward-looking statements made within the meaning of the Private

Securities Litigation Reform Act of 1995 by Anavex® Life Sciences Corp. and its representatives. These statements can be identified by introductory words such as “expects,” “plans,” “intends,” “believes,”

“will,” “estimates,” “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 potential product applications, potential collaborations, product development activities,

clinical studies, regulatory submissions and approvals, and similar operating matters. Many factors

may cause actual results to differ from forward-looking statements, including inaccurate assumptions and a broad variety of risks and uncertainties, some of which are known and others of which are not.

Known risks and uncertainties include those identified from time to time in reports filed by Anavex Life

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events, and one should avoid placing undue reliance on such statements. Anavex Life Sciences Corp.

undertakes no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise. Anavex Life Sciences Corp. cannot be sure when or if it

will be permitted by regulatory agencies to undertake clinical trials or to commence any particular

phase of clinical trials. Because of this, statements regarding the expected timing of clinical trials cannot be regarded as actual predictions 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. Potential investors should refer to the risk factors in our reports filed on Edgar.

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Sigma-1 Receptor Activation Related to Anti-Seizure Effects

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Confirmed Effects of Sigma-1 Receptor Activation …

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… effects relevant in both neurodevelopmental as well as neurodegenerative diseases

✓ Synaptogenesis

✓ Restores Ca2+ imbalance

✓ Reduces Inflammation

✓ Reduces Oxidative stress

✓ Reduces Tau hyper-phosphorylation

✓ Restores Mitochondrial dysfuncion

… as response to chronic stress caused by genetic or cellular dysfunction

Sigma-1R Agonists MoA: Restoring Homeostasis in Response to Chronic Stress Caused by Genetic or Cellular Dysfunction

ANAVEX 2-73

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

Restoring Homeostasis

Villard et al., J. Psychopharmacol. 2011

Su et al., Trends Pharmacol Sci. 2016

Sigma-1R helping / stimulating own body to regain functionality

[σ1 Antagonist]

5

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

▪ 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 supportive exploratory biomarker,

cognition and function measures correlating

▪ Dose-response relationship was statistically significant to affect MMSE-Δ and EEG/ERP-Δ scores with MMSE-Δ (p=0.0285) and EEG/ERP-Δ (p=0.0168), respectively

6Macfarlane, presented at CTAD 2016

ANAVEX®2-73: Confirmed Preclinical Data in Neurodevelopmental Genetic Disorders

Reducing mitochondrial dysfunction

Reducing protein misfolding

Reducing oxidative stress

Reducing inflammation

ANAVEX®2-73

Modulating Ca2+ Neuroprotective

Rett Syndrome (RTT)Rare neurodevelopmental disease

Preclinical validationBlinded pbo-controlled Phase 2 study

☐

Acute Epilepsy MES (seizures)Preclinical validation

AnxietyPreclinical validation

DepressionPreclinical validation

Infantile Spasms (seizures) Preclinical validation

Angelman Syndrome (seizures) Preclinical validation

Tuberous Sclerosis Complex (seizures) Preclinical validation

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Acute Epilepsy PTZ (seizures)Preclinical validation

Fragile X SyndromePreclinical validation

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Rett Syndrome (RTT): A Devastating Monogenic Disorder

▪ Rett syndrome (RTT) is caused by spontaneous (de novo) mutation in the MECP2 gene located on the X chromosome

▪ For males the gene mutation 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 function, cognitive impairment and seizures

▪ There are no approved treatments for RTT

▪ FDA granted ANAVEX®2-73 Orphan Drug Designation for RTT

Rare genetic postnatal progressive neurodevelopmental disorder

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

BDNFXMECP2 gene

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MECP2 is Mutated in Rett Syndrome Leading to Loss of Neuronal Function and Loss of BDNF

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

▪ Loss of MECP2 function alters excitatory/inhibitory synaptic balance ▪ MECP2 function required for neuronal survival, synaptic development and plasticity▪ BDNF is an important neuronal plasticity-related gene affected by loss of MECP2

Fasolino M et al., The Crucial Role of DNA Methylation and MeCP2 in Neuronal Function. 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

Rett 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

10Presented at Antiepileptic 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

Motor Impairment in Rett Syndrome

Breeding info▪ Female mice with heterozygous (HET) MECP2-null mutation#

▪ A mouse with a MECP2-null mutation causes neurological symptoms that mimic Rett syndrome

▪ Breeding done at Jackson Laboratories, mice provided at 4-5 weeks of age

MECP2 females testing at 8 and 12 weeks of age▪ 20 WT## – vehicle (0.25% MC/dH2O)▪ 20 HET – vehicle (0.25% MC/dH2O)▪ 20 HET – AV2-73 (10 mg/kg)▪ 20 HET – AV2-73 (30 mg/kg)

▪ Chronic dosing (p.o.) daily, starting at ~5.5 weeks of age and continuing through the 12-week behavioral testing time point 60 min pre-treatment during behavioral testing###

# HET = (B6.129P2(C)-MECP2(tm1.1Bird); ## WT = wild type; ### Study supported by RettSyndrome.org and performed by PsychoGenics, Inc. 11

▪ Mice are lifted gently by the tail with front limbs remaining on surface

▪ Clasping of hind legs is noted (normal is a spread in the hind legs)

Normal Impaired

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Clasping

Clasping at 8 and 12 Weeks

▪ Vehicle-treated mutant (HET) mice clasped more than vehicle-treated wild type (WT) mice (p<0.001 at 8 weeks; p<0.01 at 12 weeks)

▪ Mice treated with AV2-73 (30 mg/kg) clasped less than vehicle-treated mutant mice (p<0.05 at 8 and 12 weeks)

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Mecp2_WT Vehicle Mecp2_HET Vehicle

Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg)

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p<0.001

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Rotarod

Source: PsychoGenics, Inc. 14

Rotarod at 12 Weeks

▪ Vehicle-treated mutant (HET) mice fell significantly more rapidly and at lower speeds compared to vehicle-treated wild type (WT) mice (p<0.001)

▪ AV2-73-treated mice at both doses (10 and 30 mg/kg) took significantly more time to fall off the rod and fell at higher speeds compared to vehicle-treated mutant mice (p<0.01 and p<0.05)

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p<0.001 p<0.001p<0.01 p<0.01p<0.05 p<0.05

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NeuroCube

▪ A platform that employs computer vision to detect changes in gait geometry and gait dynamics in rodent models of neurological disorders, pain & neuropathies

▪ Mice are allowed to walk in the chamber for 5 min

▪ When the paw touches the screen, LED light reflects creating bright spots

▪ Images are captured and processed using proprietary computer vision and bio-informatics data mining algorithms


NeuroCube Body Motion Features

Body Movement Features Measurement

MinDia

DiamY500 550 600 650 700 750 800 850 900

Frame#

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Shift

Amplitude

▪ Shift – the difference between the first and the last values

▪ Amplitude – the difference between maximal and minimal values

▪ Volatility = Shift / Amplitude


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M e c p 2 _ W T V e h ic le M e c p 2 _ H E T V e h ic le

M e c p 2 _ H E T A V 2 -7 3 (1 0 m g /k g ) M e c p 2 _ H E T A V 2 -7 3 (3 0 m g /k g )

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M e c p 2 _ W T V e h ic le M e c p 2 _ H E T V e h ic le

M e c p 2 _ H E T A V 2 -7 3 (1 0 m g /k g ) M e c p 2 _ H E T A V 2 -7 3 (3 0 m g /k g )

* *

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ANAVEX®2-73: Significant Improvement of Gait

Stride Length and Front Step Length Gait to be Rescued

p<0.05 p<0.05

p<0.05p<0.01

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Gait, Correlation, Body Motion Significantly Improved

WT vehicle v.Het vehicle

Het vehicle v. Het AV2-73, 10 mg/kg

Het vehicle v.Het AV2-73, 30 mg/kg

Overall

90, p=0 53, p> 0.69 62, p> 0.24

GAIT

78, p< 0.01 63, p> 0.09 69, p< 0.05

Paw Features

91, p< 0.001 52, p> 0.78 55, p> 0.56

Correlation

53, p> 0.66 56, p> 0.40 76, p< 0.005

Body Motion

71, p< 0.02 60, p> 0.20 81, p< 0.003

Paw Positioning

84, p< 0.0001 53, p> 0.57 57, p> 0.36

Comprehensive Analysis:

Gait, Correlation, Body Motion demonstrate significant improvement

Bold represents significance 19

Startle

Image: www.med-associates.com

▪ The acoustic startle measures an unconditioned reflex response to external auditory stimulation

▪ Wild type mice have a higher startle response compared to impaired mice


Startle at 8 Weeks

▪ Vehicle-treated mutant (HET) mice startled less compared to vehicle-treated wild type (WT) mice (p<0.001)

▪ AV2-73 (30 mg/kg) treated mice showed an increased startle response compared to vehicle-treated mutant mice (p<0.05)

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Rett Syndrome Data: Optokinetic Response (OKR)

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▪ ANAXEX®2-73 (30 mg/kg po dosed daily for 4 weeks) was evaluated in the MECP2 Rett syndrome model using 7 months old mice, an age in which advanced pathology is evident

▪ The mice were tested for changes in optokinetic (automatic visual) response#

▪ Rationale

This method depends on the automatic visual response of head-tracking to a moving vertical stripe pattern presented on a rotating drum to an animal placed at its center

# The study was sponsored by Rettsyndrome.org and performed by PsychoGenics, Inc.

ANAVEX®2-73 Rescues Optokinetic Response▪ Vehicle-treated HET mice showed fewer responses than vehicle-treated WT

mice at 1.5 RPM, 2.8 RPM as well as total of both drum speeds

▪ HET mice treated with AV2-73 (30 mg/kg po) showed an increased response compared to the vehicle-treated HET mice at 1.5 RPM as well as total of both drum speeds

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#p<0.05 compared to WT vehicle group*p<0.05 compared to HET vehicle group

ANAVEX®2-73 Demonstrated a Trend related to the amount of Apneas

▪ Apneas were defined as expiratory time greater than 1 second

▪ A trend was observed in MECP2 mice treated with ANAVEX®2-73 – that is, a reduction in apnea counts to levels comparable to those observed in wild-type animals

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Infantile Spasms

▪ Infantile spasms (IS) is a seizure disorder that typically occurs during the first 4-11 months of childhood

▪ Children who develop IS are at great risk for developmental disability and autism

▪ Most children who have infantile spasms will have a very abnormal electroencephalogram (EEG) pattern called hypsarrhythymia or modified hypsarrhythmia

▪ Infantile spasms usually stop by age five, but may be replaced by other seizure types

▪ Many underlying disorders, such as birth injury, metabolic disorders, and genetic disorders can give rise to spasms, making it important to identify the underlying cause

▪ FDA granted ANAVEX®2-73 Orphan Drug Designation for IS

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Preclinical Infantile Spasms▪ The infantile spasms rat model represents a clinically relevant animal model of

infantile spasms since the phenotype is developmentally specific and semiologically similar to human infantile spasms, including clustering of spasms#

▪ The phenotype of spasms persists only up to 21 days of age in rats (correlating with human infancy and early childhood)

▪ Further, EEG features correspond well to human infantile spasms, with interictal high amplitude asynchronous waves similar to hypsarrhythmia and ictal EEG suppression similar to electrodecrements

▪ Following prenatal priming with betamethasone (gestational day 15) in infant rats, 60 minutes later NMDA (15 mg/kg i.p.) was administered to trigger spasms##

▪ Infant rats received a single pretreatment of ANAVEX®2-73 (30 mg/kg i.p.) on postnatal day 15

▪ Spasms were recorded for 90 minutes following postnatal trigger of spasms with NMDA injection

▪ The protective effects of ANAVEX®2-73 were assessed###

# Tsuji, M., et al., Epilepsia, 2016; ## Chachua, T., et al., Epilepsia, 2011. 52(9): p. 1666-77; Velisek, L., et al., Epilepsia, 2010. 51 Suppl 3: p. 145-9; ### Study supported and performed by Libor Velisek, MD, PhD, Professor of Cell Biology & Anatomy, Pediatrics, and Neurology and his laboratory at New York Medical College (NYMC) 26

ANAVEX®2-73 Significantly Reduces the Number of Spasms in a Pre-Treatment Experiment of Infantile Spasms in Infant Rat Model

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Treatment with ANAVEX®2-73 significantly reduced the number of spasms by 55% compared to vehicle

1 hour pre-treatment with ANAVEX®2-73 (30mg/kg ip) before trigger of spasms with NMDA (postnatal day 15)

Angelman Syndrome

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▪ A rare neuro-genetic disorder

▪ Majority of cases due to mutations or deletion of UBE3A gene (Chromosome 15)

▪ Affects 1:15,000

▪ Seizures (presented in over 80% of affected individuals)

▪ Ataxia

▪ Cognitive impairment

▪ Speech impairment

▪ Sleep disorders

Audiogenic Seizures in an Angelman Syndrome Model

▪ ANAVEX®2-73 (10 mg/kg ip dosed daily for 14 days) was evaluated for audiogenic-induced seizures in 3-4 month old 129-background mice with mutation in Ube3a

▪ The study was sponsored by Foundation for Angelman Syndrome. The work was carried out at the Anderson Lab at Baylor University in Houston, TX

▪ Audiogenic seizures are hypothesized to model tonic-clonic seizures with brainstem origin

− Audiogenic seizures are thought to best model temporal lobe epilepsy (TLE) and reflex seizures#

29# Kandratavicius L et al. Neuropsychiatr Dis Treat. 2014 Sep 9;10:1693-705

Partial Rescue of Audiogenic Seizure with ANAVEX®2-73

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▪ ANAVEX®2-73 administration significantly reduced audiogenic-induced seizures (p<0.01, KO vehicle vs. KO ANAVEX®2-73)

p=0.0065

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

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Presented at AES Meeting 2015, # results have been confirmed by the ETSP screening program

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

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Long-Lasting Effect Shown in PTZ-Induced Seizures

ANAVEX®2-73 also shows synergistic activity with three generations of epilepsy drugs currently on the market: ETS (Zarontin®), VPA (Depakene®) and Gabapentin (Neurontin®)

p<0.001 p<0.001

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Anti-Depressant and Anti-Anxiety Effect of ANAVEX®2-73 in Porsolt Swim Test (PST) and in Open Field Test

▪ Effect of ANAVEX®2-73 on immobility time on PST. P<0.01, *p<0.05 and **p<0.01 for 50 and 100 mg/kg vs vehicle treated group. Statistical analysis performed with ANOVA followed by Dunnett’s post-hoc test

No observed “sedative” effect of ANAVEX®2-73

▪ Effect of ANAVEX®2-73 on the number of crosses (motility-exploratory behavior) in the Open Field Test. Statistical analysis performed with ANOVA followed by Dunnett’s post-hoc test. P<0.05, **p<0.01

Presented at AES Meeting 2015 32

▪ A rare genetic disorder characterized by the growth of numerous noncancerous (benign) tumors in many parts of the body

▪ Mutations in the TSC1 or TSC2 gene can cause tuberous sclerosis complex

▪ Tuberous sclerosis complex affects about 1:6,000 people

▪ Seizures occurs in 80-90% of patients

▪ 60-80% of the seizures do not respond to antiepileptic medication

▪ Cognitive impairments

▪ CNS tumors are the leading cause of morbidity and mortality

Tuberous Sclerosis Complex

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Preclinical Tuberous Sclerosis Complex

Objective▪ This study was done to test the effect of ANAVEX®2-73 on spontaneous

seizures and mortality as compared to vehicle treatment in Tsc1GFAP

knockout mice#

Methods▪ Once daily dosing with test compounds began on Treatment Day ~D21 and

continued until ~D53: ANAVEX®2-73 (30 mg/kg/day PO), vehicle (tween 80, 5% PEG, 4% ethanol in 0.9% saline), positive control (rapamycin; 3 mg/kg/day IP)

▪ EEG headmounts were implanted between Day (D) D23-P27 and continuously recorded from D35-D53

34#The experiments were conducted at PsychoGenics Inc. in conjunction with the Tuberous Sclerosis Alliance

ANAVEX®2-73 Significantly Increases Survival of Tsc1 CKO Mice

• Tsc1 CKO mice treated with ANAVEX®2-73 (30 mg/kg/day PO) showed a significant improvement in survival compared to vehicle-treated control animals (p = 0.0008)

• In these experiments, rapamycin (3 mg/kg/day IP) served as the positive control, thus validating the results with the test compound (data not shown)

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ANAVEX®2-73 Significantly Reduces the Seizures in Tsc1 CKO Mice

• Tsc1 CKO mice treated with ANAVEX®2-73 (30 mg/kg/day PO) showed a significant reduction in seizures recorded over 48 hours (p < 0.05 vs. vehicle-treated mice)

• In these experiments, rapamycin (3 mg/kg/day IP) served as the positive control, thus validating the results with the test compound

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Seizures in the Vehicle Group Increase with Age, Which is Prevented with ANAVEX®2-73

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Summary

▪ Overall, these findings demonstrate that treating TSC1/2 mice with ANAVEX®2-73 significantly reduces seizure activity, and increases survival

▪ The anti-epileptic effect of ANAVEX®2-73 in this TSC model is consistent with the compound’s effect in four other animal seizure models, including the orphan diseases Infantile Spasms and Angelman Syndrome

▪ The results obtained in these disease models, including both chemical and genetic manipulations, suggest that targeting S1R might be of significant benefit regardless of the differences in the underlying CNS pathophysiology

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Collectively, these results suggest a role for ANAVEX®2-73 as a potential treatment for a wide range of diseases, including

rare neurodevelopmental diseases, that elicit seizures

Contact Us

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Corporate Office:Anavex™ Life Sciences Corp.51 West 52nd Street, 7th floorNew York, NY 100191-844-689-3939

Shareholder & Media Relations:Clayton RobertsonThe Trout Group(646) [email protected]: AVXL

ANAVEX is a trademark of Anavex Life Sciences Corp.

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anavex®‐7 as a potential treatment for...anavex®‐7 as a potential treatment for rett syndrome...

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