ANAVEX 2-73, a Clinical Candidate for Neurodevelopmental Disorders: New data Including AnC-Seizure data in Angelman Syndrome Christopher U Missling, PhD, President & CEO AEDD Trials XIV Conference May 2017 2 Sigma-1 Receptor AcCvaCon and NeurodegeneraCve Diseases 3 Sigma-1 Receptor AcCvaCon Related to AnC-Seizure Effects 4 Confirmed Effects of Sigma-1 Receptor AcCvaCon … ü Synaptogenesis ü Restores Ca2+ imbalance ü Reduces InflammaCon ü Reduces Oxidave stress ü Reduces Tau hyper-phosporylaon ü Restores Mitochondrial dysfuncion … effects relevant in both neurodevelopmental as well as neurodegenerave diseases 5 Sigma-1R Agonists MoA: Restoring Homeostasis ANAVEX 2-73 Sigma-1R helping / Restoring Homeostasis sCmulaCng own body to regain funcConality Su et al., Trends Pharmacol Sci. 2016 Villard et al., J. Psychopharmacol. 2011 [σ1 Antagonist] Source: Adapted from Miki et al, Dec 9. doi: 10.1111/neup.12080 Neuropathology 2013 6 Glembotski et al., Circulaon Research. 2007;101:975-984 ANAVEX™ 2-73 Shown to be Safe in Phase 2a Clinical Trial of Mild-to-Moderate Alzheimer’s PaCents § 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 supporCve exploratory biomarker, cogniCon and funcCon measures correlaCng § Low-High dose was stascally significant to affect MMSE-Δ and EEG/ERP-Δ scores with MMSE-Δ (p=0.0285) and EEG/ERP-Δ (p=0.0168), respecvely 7 Angelman Syndrome § A rare neuro-genec disorder § Majority of cases due to mutaCons or deleCon of UBE3A gene (Chromosome 15) § Affects 1 in 15,000 Symptoms include: § Seizures (presented in over 80% of affected individuals) § Ataxia § CogniCve impairment § Speech impairment § Sleep disorders 8 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 mutaCon in Ube3a § The study was sponsored by FoundaCon 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# # Kandratavicius L et al. Neuropsychiatr Dis Treat. 2014 Sep 9;10:1693-705 9 ParCal Rescue of Audiogenic Seizure with ANAVEX 2-73 § ANAVEX 2-73 administraCon significantly reduced audiogenic- induced seizures (p<0.01, KO vehicle vs. KO ANAVEX 2-73) p=0.0065 10 ANAVEX 2-73: Dose-Dependent AnC-Seizure Effects Significant Seizure Reducon with ANAVEX2-73 in Long-Lasng Effect Shown in both MES and PTZ-Induced Seizure Models PTZ-Induced Seizures p<0.001 p<0.001 100 100 90 90 80 MES-induced 80 convulsions # 70 70 60 60 50 50 4 hours PTZ-induced 40 40 6 hours convulsions 30 30 % of Seizure reducCon % of Seizure % of Seizure reducCon % of Seizure 20 20 10 10 0 0 Vehicle 10 mg/kg 30 mg/kg 100 mg/kg Vehicle 60 mg/kg (p.o.) (p.o.) (p.o.) (p.o.) ANAVEX 2-73 also shows synergisCc acvity with three generaCons of epilepsy drugs currently on the market: ETS (ZaronCn®), VPA (Depakene®) and Gabapenn (Neuronn®) Presented at AES Mee.ng 2015, # results have been confirmed by the ETSP screening program 11 ANAVEX 2-73 Significantly Reduces the Number of Spasms in a Pre-Treatment Experiment of InfanCle Spasms in Infant Rat Model 150 1 hour pre-treatment with r 100 p<0.001 ANAVEX 2-73 (30mg/kg ip) before trigger of spasms with NMDA (postnatal day 15) 50 Spasm count Spasm 0 Treatment with ANAVEX 2-73 significantly reduced the number of spasms by 55% compared to vehicle 12 Fragile X Syndrome § Rare neurodevelopmental disorder § MutaCon, CGG trinucleoCde repeats (typically >200), in the FMR1 gene cause Fragile X syndrome § AffecCng approximately 1 in 4,000 males and 1 in 6,000 females Symptoms include: § Seizures (13-44% of paCent populaCon)1 § Comorbidity with epilepsy has been found to be associated with polymorphisms in the brain-derived neurotrophic factor (BDNF) gene2 § AtenCon Problems § Anxiety § Developmental Delay § Hyperacvity 1 Berry-Kravis E. Dev Med Child Neurol. 2002 Nov;44(11):724-8 13 2 Louhivuori V et al. Epilepsy Res. 2009 Jul;85(1):114-7 BDNF Levels in Hippocampus as Biomarker § BDNF under-expression has been observed in many neurodevelopmental as well as neurodegeneraCve pathologies. BDNF signaling promotes maturaCon of both excitatory and inhibitory synapses#, and normalizaCon of BDNF expression could be beneficial in both neurodevelopmental and neurodegenerave disorders § ANAVEX 2-73 (1 mg/kg ip dosed twice daily for 14 days) was evaluated for its effect on potenCal biomarkers in 2-month old Fragile X mental retardaCon 1 knockout (Fmr1 KO) mice − BDNF protein levels in the hippocampus were measured by ELISA § The study was sponsored by FRAXA and performed by Fraunhofer Chile Research, SanCago, Chile # Castrén ML & Castrén E. Neuropharmacology. 2014 Jan;76 Pt C:729-36 14 ANAVEX 2-73 Normalizes Hippocampal BDNF Expression p<0.05 § AdministraCon of ANAVEX 2-73 in the Fragile X Fmr1 KO mouse significantly restores hippocampal BDNF expression to the same levels observed in vehicle-treated wild- type mice (p<0.05, KO vehicle vs. KO ANAVEX 2-73) 15 Ret Syndrome § Rare, non-inherited genec postnatal progressive neurodevelopmental disorder § 95% of cases due to mutaCons in MECP2 Gene (X Chromosome) § Occurs almost exclusively in girls § Affects 1 in 10,000 to 15,000 Symptoms include: § Seizures (86% in the adult paCent populaCon) § Anxiety § CogniCve impairment § Apraxia (motor speech disorder) § Loss of purposeful hand movement, stereotypic hand movement § Balance and coordinaCon issues, decrease or loss of ability to walk § Respiratory dysfuncCons "Re` Syndrome Fact Sheet", NINDS, PublicaHon date November 2009.NIH PublicaHon No. 09-4863 Image Source: Re`Syndrome.org, paent Jilly 16 Ret Syndrome Data: OptokineCc Response (OKR) § ANAXEX 2-73 (30 mg/kg po dosed daily for 4 weeks) was evaluated in the MECP2 Ret syndrome model using 7 months old mice, an age in which advanced pathology is evident § The mice were tested for changes in optokinec (automaCc visual) # response § RaConale This method depends on the automaCc visual response of head-tracking to a moving verCcal stripe patern presented on a rotaCng drum to an animal placed at its center # The study was sponsored by Re`syndrome.org and performed by PsychoGenics, Inc. 17 ANAVEX 2-73 Rescues Optokinec 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 #p<0.05 compared to WT vehicle group *p<0.05 compared to HET vehicle group 18 ANAVEX 2-73 Demonstrated a Trend related to the amount of Apneas § Apneas were defined as expiratory Cme greater than 1 second § A trend was observed in MECP2 mice treated with ANAVEX 2-73 – that is, a reducCon in apnea counts to levels comparable to those observed in wild-type animals 19 The Effects of ANAVEX 2-73 in Neurodevelopmental Disorders § Previous results have demonstrated that administraCon of ANAVEX 2-73 results in both significant and dose related improvements in an array of movement paradigms in the MECP2 HET Ret syndrome disease model and in the Fragile X Fmr1 KO disease model § The new results further suggest that ANAVEX 2-73 could be of potenCal value for the treatment of various neurodevelopmental diseases including Ret syndrome, Fragile X and Angelman syndrome Coupled with posiCve human safety and clinical cogniCon data, as well as preclinical an-seizure and an-anxiety data, ANAVEX 2-73 will be tested as a potenCal drug candidate in Ret syndrome 20 ANAVEX™ 2-73 Clinical Trial Strategy ANAVEX™2-73-001 Study: • Phase 1 (oral) • Single Ascending Dose (SAD) Completed • Healthy subjects ANAVEX™2-73-002 Study#: • Phase 2a (iv/oral) • Mild-to-moderate AD paCents More • AdapCve trial with PopulaCon PK PART A: Completed “informaCve” • PART B: Completed trial Bioavailability, dose finding (PART A), and exploratory efficacy with 52 week open-label PopulaCon PK analysis: Upcoming readout extension (PART B) ANAVEX™2-73-003 Study: • 104-week extension study aer PART B ANAVEX™2-73-101 Study: ANAVEX™2-73-004 Study: • Phase 2 (oral) • Phase 2/3 (oral) • Ret syndrome paCents • Mild-to-moderate AD paCents Preparaon underway • Double-blind, placebo controlled study • Double-blind, placebo controlled study • <3 month efficacy • 6/12 month efficacy # ClinicalTrials.gov IdenHfier: NCT02244541 21 ANAVEX 2-73 Phase 2a: 57 Week Safety Profile (MTD Study) § 32 mild-to-moderate AD paCents (baseline MMSE: 16-28) § The most common AEs at highest doses were mild dizziness followed by mild headache § Consistent with Blood Brain Barrier (BBB) penetraCon § 98% of all AEs were mild or moderate and reversible with 76% being Grade 1 § 2% were 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 resCng 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 22 2017 Clinical funding: 23 Contact Us Corporate Office: Shareholder & Media Relaons: Anavex™ Life Sciences Corp. 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