ANAVEX 2-73, a Clinical Candidate for Neurodevelopmental Disorders: New data Including An -Seizure data in Angelman Syndrome
Christopher U Missling, PhD, President & CEO AEDD Trials XIV Conference May 2017 2 Sigma-1 Receptor Ac va on and Neurodegenera ve Diseases
3 Sigma-1 Receptor Ac va on Related to An -Seizure Effects
4 Confirmed Effects of Sigma-1 Receptor Ac va on …
ü Synaptogenesis ü Restores Ca2+ imbalance ü Reduces Inflamma on ü Reduces Oxida ve stress ü Reduces Tau hyper-phosporyla on ü Restores Mitochondrial dysfuncion
… effects relevant in both neurodevelopmental as well as neurodegenera ve diseases
5 Sigma-1R Agonists MoA: Restoring Homeostasis
ANAVEX 2-73 Sigma-1R helping / Restoring Homeostasis s mula ng own body to regain func onality
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., Circula on Research. 2007;101:975-984 ANAVEX™ 2-73 Shown to be Safe in Phase 2a Clinical Trial of Mild-to-Moderate Alzheimer’s Pa ents § 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 suppor ve exploratory biomarker, cogni on and func on measures correla ng § Low-High dose was sta s cally significant to affect MMSE-Δ and EEG/ERP-Δ scores with MMSE-Δ (p=0.0285) and EEG/ERP-Δ (p=0.0168), respec vely
7 Angelman Syndrome
§ A rare neuro-gene c disorder § Majority of cases due to muta ons or dele on of UBE3A gene (Chromosome 15) § Affects 1 in 15,000
Symptoms include: § Seizures (presented in over 80% of affected individuals) § Ataxia § Cogni ve 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 muta on in Ube3a § The study was sponsored by Founda on 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 Par al Rescue of Audiogenic Seizure with ANAVEX 2-73 § ANAVEX 2-73 administra on significantly reduced audiogenic- induced seizures (p<0.01, KO vehicle vs. KO ANAVEX 2-73)
p=0.0065
10 ANAVEX 2-73: Dose-Dependent An -Seizure Effects
Significant Seizure Reduc on with ANAVEX2-73 in Long-Las ng 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 reduc on % of Seizure % of Seizure reduc on % 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 synergis c ac vity with three genera ons of epilepsy drugs currently on the market: ETS (Zaron n®), VPA (Depakene®) and Gabapen n (Neuron n®)
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 Infan le Spasms in Infant Rat Model
150
1 hour pre-treatment with 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 § Muta on, CGG trinucleo de repeats (typically >200), in the FMR1 gene cause Fragile X syndrome § Affec ng approximately 1 in 4,000 males and 1 in 6,000 females
Symptoms include: § Seizures (13-44% of pa ent popula on)1 § Comorbidity with epilepsy has been found to be associated with polymorphisms in the brain-derived neurotrophic factor (BDNF) gene2 § A en on Problems § Anxiety § Developmental Delay § Hyperac vity
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 neurodegenera ve pathologies. BDNF signaling promotes matura on of both excitatory and inhibitory synapses#, and normaliza on of BDNF expression could be beneficial in both neurodevelopmental and neurodegenera ve disorders § ANAVEX 2-73 (1 mg/kg ip dosed twice daily for 14 days) was evaluated for its effect on poten al biomarkers in 2-month old Fragile X mental retarda on 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, San ago, Chile
# Castrén ML & Castrén E. Neuropharmacology. 2014 Jan;76 Pt C:729-36 14 ANAVEX 2-73 Normalizes Hippocampal BDNF Expression
p<0.05
§ Administra on 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 Re Syndrome § Rare, non-inherited gene c postnatal progressive neurodevelopmental disorder § 95% of cases due to muta ons 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 pa ent popula on) § Anxiety § Cogni ve impairment § Apraxia (motor speech disorder) § Loss of purposeful hand movement, stereotypic hand movement § Balance and coordina on issues, decrease or loss of ability to walk § Respiratory dysfunc ons "Re Syndrome Fact Sheet", NINDS, Publica on date November 2009.NIH Publica on No. 09-4863 Image Source: Re Syndrome.org, pa ent Jilly 16 Re Syndrome Data: Optokine c Response (OKR)
§ ANAXEX 2-73 (30 mg/kg po dosed daily for 4 weeks) was evaluated in the MECP2 Re syndrome model using 7 months old mice, an age in which advanced pathology is evident
§ The mice were tested for changes in optokine c (automa c visual) # response
§ Ra onale This method depends on the automa c visual response of head-tracking to a moving ver cal
stripe pa ern presented on a rota ng 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 Optokine c 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 me greater than 1 second § A trend was observed in MECP2 mice treated with ANAVEX 2-73 – that is, a reduc on 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 administra on of ANAVEX 2-73 results in both significant and dose related improvements in an array of movement paradigms in the MECP2 HET Re syndrome disease model and in the Fragile X Fmr1 KO disease model
§ The new results further suggest that ANAVEX 2-73 could be of poten al value for the treatment of various neurodevelopmental diseases including Re syndrome, Fragile X and Angelman syndrome
Coupled with posi ve human safety and clinical cogni on data, as well as preclinical an -seizure and an -anxiety data, ANAVEX 2-73 will be tested as a poten al drug candidate in Re 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 pa ents More • Adap ve trial with Popula on PK PART A: Completed “informa ve” • PART B: Completed trial Bioavailability, dose finding (PART A), and exploratory efficacy with 52 week open-label Popula on PK analysis: Upcoming readout extension (PART B) ANAVEX™2-73-003 Study:
• 104-week extension study a er PART B
ANAVEX™2-73-101 Study: ANAVEX™2-73-004 Study: • Phase 2 (oral) • Phase 2/3 (oral) • Re syndrome pa ents • Mild-to-moderate AD pa ents Prepara on underway • Double-blind, placebo controlled study • Double-blind, placebo controlled study • <3 month efficacy • 6/12 month efficacy
# ClinicalTrials.gov Iden fier: NCT02244541 21 ANAVEX 2-73 Phase 2a: 57 Week Safety Profile (MTD Study)
§ 32 mild-to-moderate AD pa ents (baseline MMSE: 16-28)
§ The most common AEs at highest doses were mild dizziness followed by mild headache § Consistent with Blood Brain Barrier (BBB) penetra on § 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 res ng 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:
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