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1 Fr persnal use nly NNZ-2566 Prgram Presented at Internatinal Autism Cnference SYDNEY, Australia, 7 August 2012: Dr Michael Snape, Chief Scientific Officer f Autism Therapeutics Ltd, gave a presentatin n NNZ-2566 and the ratinale fr its use in autism spectrum disrders at the ICare4Autism 2012 Internatinal Autism Cnference in Jerusalem. Autism Therapeutics Ltd is supprting preparatins fr the clinical trials in Rett Syndrme and develpment f NNZ-2566 in autism spectrum disrders under cntract t Neuren Pharmaceuticals Limited (ASX: NEU). A cpy f the presentatin is attached t this annuncement and will be psted n Neuren s website Abut Rett Syndrme Rett Syndrme is a pst-natal neurlgical disrder which ccurs almst exclusively in females fllwing apparently nrmal develpment fr the first six mnths f life. Typically, between 6 t 18 mnths f age, patients experience a perid f rapid decline with lss f purpseful hand use and spken cmmunicatin. Many patients have recurrent seizures. They experience a variety f mtr prblems including increased muscle tne (spasticity) and abnrmal mvements. They are never able t prvide fr their wn needs. It is a rare disrder and is believed t be secnd nly t Dwn Syndrme as a cause f chrnic neurlgical prblems that include severe cmmunicatin, mtr disabilities and epilepsy. Rett Syndrme is caused by mutatins n the X chrmsme f a gene called MECP2. There are mre than 200 different mutatins fund n the MECP2 gene. Rett Syndrme strikes all racial and ethnic grups, and ccurs wrldwide in up t 1 f every 10,000 female births and affects sme 15,000 girls and wmen in the U.S. alne. Abut Neuren Neuren Pharmaceuticals is a bipharmaceutical cmpany develping new therapies fr brain injury, neurdevelpmental and neurdegenerative disrders and cancer. Neuren presently has tw clinical-stage mlecules, NNZ-2566 and Mtiva, in Phase 2 clinical trials largely funded by the US Army and the Natinal Health and Medical Research Cuncil, respectively. Thrugh its subsidiary, Perseis Therapeutics Limited, Neuren is develping mnclnal antibdies against Trefil Factrs 1 and 3, prteins prduced by cancer cells that are assciated with cancer spread and reduced patient survival. Fr mre infrmatin, please cntact: Larry Glass, Neuren CEO lglass@neurenpharma.cm Tel:

2 Fr persnal use nly NNZ-2566 Ratinale fr use in Autism Spectrum Disrders 1

3 Fr persnal use nly Overview Autism: a disrder f synaptic cnnectivity invlving neurinflammatin Bth synaptic cnnectivity and neurinflammatry prcesses may invlve the PI3K-Akt-mTR pathway The natural grwth factr IGF-1 is brken dwn in the bdy t IGF-1[1-3] r Glyprmate. Glyprmate and NNZ-2566 act t reduce neurinflammatin. These effects may be mediated by mdulatin f the PI3K-Akt-mTR pathway. NNZ-2566 is an analgue f Glyprmate develped by Neuren Pharmaceuticals Ltd. NNZ-2566 has enhanced ral availability and a pharmaceutical prfile suitable fr investigatin in autism spectrum disrders. Clinical studies are planned by Neuren 02/08/2012 2

4 Fr persnal use nly Autism Hetergeneus disrder Heavily genetically influenced Genes affected cmmnly relate t synaptic r immune functin 1 1 Vineagu et al (2011) Nature 474:380 02/08/2012 3

5 Neurnal Signalling Pathways CAMKII NMDA R PTEN EAA PSD 95 NEUREXIN-NEUROGLIN PI3K AMPA R HOMER PDZ SHANK MGLU R TRAF2 ASK TNF CT R Fr persnal use nly EAA Grb2 SOS CADHERIN CATENIN ACAP BDNF TRKB R MET RAS CD44 NF1 HGF Neural functin relies n plasticity f synaptic cnnectins Intraneurnal pathways underlying plasticity well understd MECP2 DHCR RAC AKT PAK RAF TSC1-TSC2 FMRP APP RAPTOR MEKK MEK TAO2ß MEK MEKK Pathways invlve e.g. Ras-MEK-ERK r PTEN-Akt-mTR 2 mtor p38 ERK MK2 MSK RSK LIMK CREB 2 Kelleher et al (2004) Neurn 44:59 COFILIN Cell Cycle ACTIN Neurnal Mrphlgy 02/08/2012 4

6 Fr persnal use nly Mapping ASDs nt Signalling Pathways 02/08/2012 5

7 Fr persnal use nly Synapses in ASDs Altered synapses in idipathic 3 and syndrmic autism 4,5 3 Hutsler and Zhang (2010) Brain Res 1309:83 4 Irwin et al (2000) Cerebral Crtex 10: Chapleau et al (2009) Neurbil Dis 35:219 02/08/2012 6

8 Fr persnal use nly Neurinflammatin Neurns supprted within the brain by micrglia 6 Micrglia have a diverse range f functins 7 including: Regulatin f transmitters e.g. glutamate Remval damaged tissue Regulatin f synapses 6 Mnk and Shaw (2006) Nat Med 12:885 7 Hughes (2012) Nature 485:570 02/08/2012 7

9 Fr persnal use nly Neurinflammatin in ASDs Micrglia and astrglia are activated in brain in autism 8 Fragile X Syndrme astrcytes can institute neurnal phentype 9 Micrglia in Rett Syndrme 10 8 Vargas et al (2005) Ann Neurl. 57:67 9 Jacbs et al (2010) BMC Neursci. 11: Maezawa and Jin (2010) J Neursci. 30: /08/2012 8

10 Fr persnal use nly Cytkines in ASDs Cytkines are cell signalling mlecules prduced by immune system cells including micrglia Interleukin-6 is an example. Interleukin-6 may be invlved in autism 11, Fragile X Syndrme 12 and Rett Syndrme 13 Interleukin-6 can activate micrglia 14 IL-6 induces changes in dendritic spine density and reduces scial interactin in an animal mdel f autism Ashwd et al (2011) Brain Behav Immun. 25:40 12 Ashwd et al (2010) Brain Behav Immun. 24: De Filippis et al (2012) Neurpsychpharmaclgy 37: Krady et al (2008) J Neursci Res. 86: Wei et al (2012) Bichim Biphys Acta. 1822:831 02/08/2012 9

11 Fr persnal use nly Summary Idipathic and syndrmic ASDs invlve: Neurinflammatin Changes in cytkines such as IL-6 Altered micrglial functin Aberrant cntrl f synapse frmatin Ptentially via the Akt-mTR pathway Interventins that address these issues may have therapeutic utility 02/08/

12 Fr persnal use nly IGF-1 Insulin like grwth factr 1 (IGF-1) is a natural grwth factr that has many functins in cntrlling grwth, including neurns and synapses. IGF-1 is altered in autism 16, may rescue functin in Rett Syndrme 17 and in ASD caused by changes in the shank3 gene 18 : 16 Riiknen (2003) J Child Neurl Trpea et al. 2009, PNAS Buxbaum et al 02/08/

13 Fr persnal use nly IGF-1[1-3] IGF-1 is metablized in the bdy Endgenus peptidase enzymes cleave IGF-1, separating the terminal tripeptide The terminal tripeptide knwn as IGF- 1[1-3] r Glyprmate rescues functin in the mecp2 muse mdel f Rett Syndrme Trpea et al. (2009) PNAS 106: /08/

14 Fr persnal use nly IGF-1[1-3] Mechanism f Actin IGF-1[1-3] (Glyprmate): Reduces cytkines 20 and neurinflammatry markers in brain 21 Activates Akt-mTR pathway in micrglia 22 Increases markers f presynaptic and pstsynaptic synapses 23 Activates Akt-mTR pathway in mecp2 knckut muse mdel f Rett Syndrme 22 IGF[1-3] reduces number f micrglia in hippcampus fllwing hypxia ischemia in rat brain Casandra et al (2011) 21 Guan et al (2004) Neurpharmaclgy 47: Trpea et al. (2009) PNAS 106: Crvin et (2012) Neursci Lett. 520:51 02/08/

15 Fr persnal use nly IGF-1[1-3] Mechanism f Actin IGF-1[1-3] (Glyprmate) increases dendritic spine density in mecp2 muse mdel f Rett Syndrme 24 IGF-1[1-3] (Glyprmate) increases pre- and pst- synaptic markers Crvin et (2012) Neursci Lett. 520:51 25 Trpea et al. (2009) PNAS 106: /08/

16 Fr persnal use nly NNZ-2566 Clinical study f IGF-1 (InCrelexunderway 26 IGF-1 (InCrelexavailable and may nt penetrate int brain 27 NNZ-2566 is IGF-1[1-3] mdified t be rally available and penetrate the brain 28 NNZ-2566 may act n cytkines such as IL-6 29 Orally available Brain penetrant EMEA Scientific Discussin Increlex 28 Bickerdike et al (2009) J Neurl Sci. 278:85 29 Casandra et al (2011) 02/08/

17 Fr persnal use nly Summary ASDs may invlve alteratins in: Synaptic functin Neurinflammatin the Akt-mTR pathway IGF-1 and Glyprmate is a natural grwth factr that: May act via the Akt-mTR pathway Reduces neurinflammatin Rescues deficits in the synapse Acts in transgenic mdels f ASDs NNZ-2566 Mdified frm f IGF-1[1-3] suited t medicinal use Currently planned fr clinical investigatin in Rett Syndrme 02/08/