Assessment of ANAVEX 2-73 in a MECP2 Re5 Syndrome Mouse Model

Transcription

1 Assessment of ANAVEX 2-73 in a MECP2 Re5 Syndrome Mouse Model 2016 Epilepsy Pipeline Conference February 26 th 2016

2 Safe Harbor This presenta,on contains forward- looking statements made within the meaning of the Private Securi,es Li,ga,on Reform Act of 1995 by Anavex Life Sciences Corp. and its representa,ves. These statements can be iden,fied by introductory words such as ``expects,'' ``plans,'' ``intends,'' ``believes,'' ``will,'' ``es,mates,'' ``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 poten,al product applica,ons, poten,al collabora,ons, product development ac,vi,es, clinical studies, regulatory submissions and approvals, and similar opera,ng maners. Many factors may cause actual results to differ from forward- looking statements, including inaccurate assump,ons and a broad variety of risks and uncertain,es, some of which are known and others of which are not. Known risks and uncertain,es include those iden,fied from,me to,me in the reports filed by Anavex Life Sciences Corp. with the Securi,es 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 obliga,on to update publicly any forward- looking statements, whether as a result of new informa,on, future events or otherwise. Anavex Life Sciences Corp. cannot be sure when or if it will be permined by regulatory agencies to undertake clinical trials or to commence any par,cular phase of clinical trials. Because of this, statements regarding the expected,ming of clinical trials cannot be regarded as actual predic,ons 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. Poten,al investors should refer to the risk factors in our reports filed on Edgar. 2

3 Re5 Syndrome ReN syndrome is a rare non- inherited gene,c postnatal progressive neurodevelopmental disorder that occurs almost exclusively in girls and leads to severe impairments Affec,ng nearly every aspect of the child s life: their ability to speak, walk, eat, and even breathe easily It is caused by muta,ons in X- linked MECP2, encoding methyl- CpG- binding protein 2 It is characterized by normal early growth and development (6 to 18 months) followed by a slowing of development, loss of purposeful use of the hands, dis,nc,ve hand movements, slowed brain and head growth, problems with walking, seizures #, and intellectual disability ReN syndrome strikes all racial and ethnic groups and occurs worldwide in approximately 1 in every 10,000-15,000 live female births # 84% of Re/ syndrome pa8ents age experience seizures (Glaze DG et al. Neurology Mar 16; 74(11): ) 3

4 ANAVEX 2-73 Currently in a Phase 2a clinical trial for Alzheimer s disease (AD) ANAVEX 2-73 is an orally available small molecule targe,ng protein misfolding and cellular stress, factors in neurodegenerakve diseases through ac,va,ng Sigma- 1 Receptor Phase 2a (PART A) results demonstrate a favorable safety, bioavailability, dose- response curve and tolerability/risk profile Suppor,ve evidence indica,ng a cogni,ve benefit associated with ANAVEX 2-73 (Cogstate, MMSE, EEG/ERP improved sta,s,cally significantly at 5 weeks of treatment) Guidance received from the FDA supports the Company s plan to advance ANAVEX 2-73 for the treatment of Alzheimer s disease in a larger double- blinded, randomized, placebo- controlled Phase 2/3 trial Phase 2a PART B 52 week extension trial is ongoing Addi,onal data, including updates on PART B to be presented at upcoming scien,fic mee,ngs 4

5 Sigma- 1 Receptor: Upstream Pluripotent Modulator ANAVEX2-73 Enabling neuroprotec,on Modula,ng Ca 2+ Reducing mitochondrial dysfunc,on Blocking NOS Reducing protein misfolding Reducing oxida,ve stress Reducing inflamma,on Su et al., Trends Pharmacol Sci Feb 8. pii: S (16) ; Cauli et al., Neuroscience, Volume 190, 2011, Pages 27-36; Miki et al, Dec 9. doi: /neup Neuropathology 2013; Glembotski et al., Circula8on Research. 2007;101:

6 ANAVEX 2-73 Pre- Clinical Epilepsy Data % of Seizure reduckon Significant Seizure Reduc,on with ANAVEX2-73 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<0.001 MES- induced # convulsions PTZ- induced convulsions Long- Las,ng Effect Shown in PTZ- Induced Seizures % of Seizure reduckon Vehicle *** *** 60 mg/kg (p.o.) 4 hours 6 hours ANAVEX 2-73 also shows synergis8c 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 Mee8ng 2015, # results have been confirmed by the NINDS screening program 6

7 AnK- Depressant and AnK- Anxiety Effect of ANAVEX 2-73 in Porsolt Swim Test (PST) and in Open Field Test No observed sedakve effect of ANAVEX 2-73 Effect of ANAVEX2-73 on immobility,me on PST. P<0.01, *p<0.05 and **p<0.01 for 50 and 100 mg/kg vs vehicle treated group. Sta,s,cal analysis performed with ANOVA followed by DunneN s post- hoc test Effect of ANAVEX2-73 on the number of crosses (mo,lity- exploratory behavior) in the Open Field Test. Sta,s,cal analysis performed with ANOVA followed by DunneN s post- hoc test. P<0.05, **p<0.01 Presented at AES Mee8ng

8 Preclinical Re5 Syndrome Breeding info Female mice with heterozygous (HET) MECP2- null muta,on # A mouse with a MECP2- null muta,on causes neurological symptoms that mimic ReN syndrome Breeding done at Jackson Laboratories, mice provided at 4-5 weeks of age MECP2 females teskng at 8 and 12 weeks of age 20 WT ## vehicle (0.25% MC/dH 2 O) 20 HET vehicle (0.25% MC/dH 2 O) 20 HET AV2-73 (10 mg/kg) 20 HET AV2-73 (30 mg/kg) Chronic dosing (p.o.) daily, star,ng at ~5.5 weeks of age and con,nuing through the 12- week behavioral tes,ng,me point 60 min pre- treatment during behavioral tes,ng Experiment was performed by PsychoGenics, Inc. # HET = (B6.129P2(C)- MECP2(tm1.1Bird), ## WT = wild type 8

9 Clasping Mice are lixed 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 9

10 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) Clasping at 8 weeks Clasping at 12 weeks Clasping Hindlimbs (%) p<0.001 *** p<0.05 * Clasping Hindlimbs (%) p<0.01 ** p<0.05 * Mecp2_WT Vehicle Mecp2_HET Vehicle Mecp2_WT Vehicle Mecp2_HET Vehicle Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg) Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg) 10

11 Startle The acous,c startle measures an uncondi,oned reflex response to external auditory s,mula,on Wild type mice have a higher startle response compared to impaired mice Source: PsychoGenics, Inc. Image: 11

12 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) 600 Mean Startle Response p<0.001 *** p<0.05 * 0 Mecp2_WT Vehicle Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET Vehicle Mecp2_HET AV2-73 (30 mg/kg) 12

13 Rotarod Source: PsychoGenics, Inc. 13

14 Rotarod at 12 Weeks Latency to Fall (s) 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,me to fall off the rod and fell at higher speeds compared to vehicle- treated mutant mice (p<0.01 and p<0.05) p<0.001 *** p<0.01 p<0.05 ** * Speed at Fall (rpm) p<0.001 *** p<0.01 p<0.05 ** * Mecp2_WT Vehicle Mecp2_HET Vehicle Mecp2_WT Vehicle Mecp2_HET Vehicle Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg) Mecp2_HET AV2-73 (10 mg/kg) Mecp2_HET AV2-73 (30 mg/kg) 14

15 NeuroCube Source: PsychoGenics, Inc. A plazorm 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 crea,ng bright spots Images are captured and processed using proprietary computer vision and bio- informa,cs data mining algorithms 15

16 NeuroCube Body MoKon Features 120 Body Movement Features Measurement Shift Amplitude Frame# MinDia DiamY Shix the difference between the first and the last values Amplitude the difference between maximal and minimal values Vola,lity = Shix / Amplitude Source: PsychoGenics, Inc. 16

17 NeuroCube at 8 Weeks Some gait differences appear to be rescued p<0.05 p<0.05 S tr id e L e n g th (m m ) p<0.01 * * * F r o n t S te p L e n g th (m m ) p<0.05 * * M ecp2 _ W T V ehicle M ecp2_h ET Vehicle M ecp2 _ W T V ehicle M ecp2_h ET Vehicle M ecp2 _ H E T A V2-73 (10 m g /kg) M ecp2 _ H E T A V2-73 (30 m g /kg) M ecp2 _ H E T A V2-73 (10 m g /kg) M ecp2 _ H E T A V2-73 (30 m g /kg) 17

18 NeuroCube at 8 Weeks Comprehensive Analysis: Gait, CorrelaKon, Body MoKon demonstrate significant improvement Overall GAIT Paw Features CorrelaKon Body MoKon Paw PosiKoning WT vehicle v. Het vehicle Het vehicle v. Het AV2-73, 10 mg/kg Het vehicle v. Het AV2-73, 30 mg/kg 90, p=0 53, p> , p> , p< , p> , p< , p< , p> , p> , p> , p> , p< , p< , p> , p< , p< , p> , p> 0.36 Bold represents significance 18

19 Summary Administra,on of ANAVEX 2-73 results in both significant and dose related improvements in an array of behavioral paradigms in the MECP2 HET ReN syndrome disease model Taken together, these behavioral paradigms measure different aspects of muscular coordina,on, balance, motor learning and muscular strengths, some of the core deficits observed in ReN syndrome Coupled with posi,ve human safety and cogni,on data, as well as preclinical an,- seizure and an,- anxiety data, ANAVEX 2-73 might be a poten,al drug candidate to inves,gate in ReN syndrome 19