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

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

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

Arenicin interacts with the lipid transporter protein 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

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 min induced loss of cell surface structures and partial clearing of cytoplasm Bar, 200 nm University of Queensland 2013 6

Arenicin causes ATP release without dramatic changes in cell morphology 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. Extracellular ATP after 10 min x MIC Fold change Arenicin-3 (Ar), colistin (col), and piperacillin (pip) induced release 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

Arenicin and Colistin have different effects on osmotic shock genes Symbol Gene ID Colistin µg/ml Arenicin µg/ml Description 2½ 5 10 Osmotic shock genes osmB B1283 63 29 8 3 lipoprotein, osmotically inducible, osmC B1482 - Peroxiredoxin osmY B4376 Osmotically-inducible protein Y precursor osmE B1739 Osmotically-inducible lipoprotein E precursor bdm B1481 11 6 Biofilm-dependent modulation proteinosmotically inducible sra B1480 4 rpsV, osmotically inducible rcsA B1951 2 positive regulator for ctr capsule biosynthesis, Whole Genome TraDIS preliminary data suggest inhibition of key cytosolic processes in gene translation Novozymes A/S, 2010 8

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 No synergistic or antagonistic effect with other antibiotics No cross resistance with strains with acquired resistance to Colistin 9

Potent in vitro activity against GAIN pathogens MIC90 determinations (MDR clinical isolates) # strains AA139 Colistin Meropenem Ceftazidime Ciprofloxacin Gentamicin Tigecycline N=325 MIC (µg/ml) E.coli N=55 1 0.25 4 >32 >4 0.5 K.pneumonia N=75 8 >16 P.aeruginosa 2 ND A.baumanii N=120 Eurofins medinet 2012 10

Extremely low spontaneous mutational frequency to Arenicin Organism Isolate ID Resistance Frequency (4XMIC) Resistance Frequency (8XMIC) AA139 E. coli ATCC 25922 ≤2,50E-12 3083559 ≤8,90E-11 K. pneumoniae 3083832 ≤4,16E-10 3083583 ≤1,38E-11 P. aeruginosa ATCC 27853 ≤2,61E-12 3083655 ≤2,68E-12 A. baumannii 3083835 ≤2,65E-12 3083684 ≤4,80E-10 Eurofins medinet 2012 11

Limited effect of mucin (Survanta) on in vitro efficacy NBS plates- MHB only Compound ID GN_01 E.coli ATCC 25922 GN_03 K. pneumoniae ATCC 700603 GN_04 ATCC 13883 GN_34 A.baumannii ATCC 19606 GN_42 P.aeruginosa ATCC 27853 GN_43 Polymixin R GN_44 ATCC 10536 GN_45 BAA_2146 MIC [μg/mL] Colistin MCC_000094B ≤0.03 0.03/0.06 1/2 32/64 0.03/0.125 0.06 Ciprofloxacin  MCC_000166 0.25 0.5/1 2 0.25/0.5 >64 AA139 0.5 0.125/0.25 0.125 NBS plates-  MHB + 5% Survanta Compound ID MIC [μg/mL] Colistin MCC_000094B 0.06 1/0.5 0.125 0.5/0.25 0.5 64 Ciprofloxacin  MCC_000166 ≤0.03 2 >64 1 2/1 AA139 0.125/0.06 16/8 8x MIC increase Decrease in MIC University of Queensland 2013 12

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

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

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 pneumonia based on aerosol administration 15

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

Klebsiella Pneumonia NCTC13442 Very good activity of Arenicin against K. pneumonia in a neutropenic pneumonia model following aerosol admin Klebsiella Pneumonia NCTC13442 Variant log reduction MIC AA139 -3.89 1 Colistin -1.75 Euprotec 2013 17

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

Product profiles of Meropenem, Colistin and Arenicin Indications Meropenem Colistin Arenicin Pneumonia +++ Complicated urinary tract infections Coverage XDR E.coli ++ XDR P.aeruginosa XDR A.baumannii + KPC K.pneumonia - Colistin G- Bacteria Administration Oral no IV yes IT Adverse events Renal/Hepatic (yes) (no) Neurological Hypersensitivity Miscellaneous Bactericidal 19