anavex®‐7 as a potential treatment for...anavex®‐7 as a potential treatment for rett syndrome...
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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
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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]
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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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Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg)
**
*
Clasping at 8 weeks Clasping at 12 weeks
p<0.001
p<0.05
p<0.05
p<0.01
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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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Mecp2_WT Vehicle Mecp2_HET Vehicle
Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg)
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Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg)
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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
Source: PsychoGenics, Inc. 16
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
Source: PsychoGenics, Inc. 17
3 0
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3 8
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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 )
4 0
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7 0
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(m
m)
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 )
* *
*
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
Source: PsychoGenics, Inc. 20
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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Mecp2_WT Vehicle Mecp2_HET Vehicle
Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg)
***
*p<0.05p<0.001
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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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MES-inducedconvulsions
PTZ-inducedconvulsions
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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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60 mg/kg (p.o.)
Vehicle
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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edu
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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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