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Corporate presentation,October 2013

Corporate presentation,October 2013. Ideal Target Product Profile for multidrug resistant broad spectrum Gram-negative antimicrobial. Novel mode of action Bactericidal Selective and specific Low frequency of resistance Active against GAIN pathogens Drugable. 2. Arenicin selection process.

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Corporate presentation,October 2013

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  1. Corporate presentation,October 2013

  2. Ideal Target Product Profile for multidrug resistant broad spectrum Gram-negative antimicrobial Novel mode of action Bactericidal Selective and specific Low frequency of resistance Active against GAIN pathogens Drugable 2

  3. Arenicin selection process > 500 organisms screened for antimicrobial activity 1500 hits but only 10 variants selected Several G+ but only one G- identified ! NZ17074 First Hit Clin Cand – AA139 Second variant library (~90.000 variants) Variant library generation (~250.000 variants) ~40 AMP’s identified 3

  4. Mode of action summary • Arenicin acts at least partly due to non-lipid A-mediated penetration and disruption of both Gram negative membranes • Inhibition of cytosolic processes in protein synthesis suggested in TraDIS studies • Arenicins mode of action is different from Colistins 4

  5. Arenicininteractswith the lipidtransporterprotein MLAC • MlaC is a periplasmic binding protein maintaining phospholipid homeostasis of the dual cell membrane • Gene analysis of E.coli shows that an MlaC L11R mutation is required to prevent the interaction between Arenicin and MlaC • Resistant strains regain sensitiviy to Arenicin as mutant is not stable 5

  6. Arenicin causes loss of cell surface structure and partial cytoplasm clearing in E. coli Transmission Electron Microscopy (TEM) of the Arenicin effect on E.coli (ATCC 25922) E.coli. No treatment. Black arrow, cytoplasmic membrane; Red arrow, outer membrane; Green arrow, pili. Bar, 200 nm E. coli incubated with 32 μg/mL NZ17000 for 40 mininduced loss of cell surface structures and partial clearing of cytoplasm Bar, 200 nm University of Queensland 2013 6

  7. Arenicin causes ATP release without dramatic changes in cell morphology Extracellular ATP after 10 min Fold change At OD600 =0.4 E.coli cells were exposed to 32ug/ml Arenicin, 64ug/ml Fosfomycin and 16ug/ml Polymycin B. Even at very high concentration of Arenicin-3, no dramatic morphological changes of the cells were observed. x MIC Arenicin-3 (Ar), colistin (col), and piperacillin (pip) inducedrelease of ATP from E. coli. Exponential cells were incubated with drug for 10 minutes and ATP measured. y-axis is fold change relative to untreated (0xmic) and x-axis is fold MIC applied. Novozymes A/S, 2010 7

  8. Arenicin and Colistin have different effects on osmotic shock genes Whole Genome TraDIS preliminary data suggest inhibition of key cytosolic processes in gene translation Novozymes A/S, 2010 8

  9. In vitro efficacy summary • Potent in vitro activity against GAIN pathogens • Rapidly bactericidal – MBCs ~ MICs • Extremely low spontaneous mutational frequency • Small and mostly reversible increase of MIC in serial passage studies comparable with Colistin • Little inoculum effect • Moderate effect of serum on MIC • Limited effect of Survanta on MIC • Nosynergistic or antagonistic effect with other antibiotics • No cross resistance with strains with acquired resistance to Colistin 9

  10. Potent in vitro activity against GAIN pathogens MIC90 determinations (MDR clinical isolates) Eurofins medinet 2012 10

  11. Extremely low spontaneous mutational frequency to Arenicin Eurofins medinet 2012 11

  12. Limited effect of mucin (Survanta) on in vitro efficacy 8x MIC increase Decrease in MIC University of Queensland 2013 12

  13. Pharmacokinetic/pharmacodynamic summary • Arenicin efficacy is driven by Cmax • Clinical therapy should thus be based on slow bolus injection • Hepatic clearance does not seem to play a role • AA139 has a good volume of distribution corresponding to the extracellular volume • AA139 has a half life of 4.3 hours • AA139 has a low penetration into ELF (<5%) 13

  14. PK/PD dose fractionation study shows that Cmax drives the efficacy of Arenicin (NZ17230) (5mg/kg over 3 days seems to exert maximal effect) Euprotec 2013 14

  15. In vivo efficacy summary • Excellent efficacy against K.pneumoniae and E.coli in UTI with ED50 of 0.5-1mg/kg (BID I.V. administration) • Modest efficacy against K.pneumoniae, P.aeruginosa and A. baumannii in pneumonia based on QID I.V. administration • Very good efficacy against K.pneumoniae in pneumoniabased on aerosol administration 15

  16. Excellent efficacy in UTI ED50 for AA139 in the bladder E. coli K. pneumonia Euprotec 2013 16

  17. Very good activity of Arenicin against K. pneumoniain a neutropenic pneumonia model following aerosol admin Euprotec 2013 17

  18. Toxicological summary • Selective and specific for bacteria • Wide therapeutic window – a factor of 25 • MTD level of 25 mg/kg versus ED 50 of 1 mg/kg • Adverse effects related to histamin release • Changes in proximal tubuli the only, dose dependent and reversible pathological finding • Changes in NGAL correspond with pathological kidney findings • No cardiotoxic effect 18

  19. Product profiles of Meropenem, Colistin and Arenicin 19

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