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Corporate presentation,October 2013

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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

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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

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Clin Cand – AA139

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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

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• 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

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Arenicin interacts with the lipid transporter protein MLAC

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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

6University of Queensland 2013

Arenicin causes loss of cell surface structure and partial cytoplasm clearing in E. coli

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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.

0 16 64 256 1024 40960

5

10

15

20

25

Arcolpip

Extracellular ATP after 10 min

x MIC

Fold

cha

nge

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.

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Novozymes A/S, 2010

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Arenicin and Colistin have different effects on osmotic shock genes

Symbol Gene ID

Colistin µg/ml

Arenicin µg/ml

Description2½ 2½ 5 10

Osmotic shock genesosmB B1283 63 29 8 3 lipoprotein, osmotically inducible,osmC B1482 10 - - - PeroxiredoxinosmY B4376 5 - - - Osmotically-inducible protein Y precursorosmE B1739 3 - - - Osmotically-inducible lipoprotein E precursorbdm B1481 63 11 6 3 Biofilm-dependent modulation proteinosmotically inducible

sra B1480 11 4 3 - rpsV, osmotically induciblercsA B1951 6 2 - - positive regulator for ctr capsule biosynthesis,

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Novozymes A/S, 2010

Whole Genome TraDIS preliminary data suggest inhibition of key cytosolic processes in gene translation

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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

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# strains AA139 Colistin Meropenem Ceftazidime Ciprofloxacin Gentamicin Tigecycline

N=325 MIC (µg/ml)

E.coli N=55 1 0.25 4 >32 >4 >32 0.5

K.pneumonia N=75 4 8 >16 >32 >4 >32 4

P.aeruginosa N=75 8 2 >16 >32 >4 >32 ND

A.baumanii N=120 2 8 >16 >32 >4 >32 4

Potent in vitro activity against GAIN pathogens

MIC90 determinations (MDR clinical isolates)

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Extremely low spontaneous mutational frequency to Arenicin

Organism Isolate ID

Resistance Frequency

(4XMIC)

Resistance Frequency

(8XMIC)AA139 AA139

E. coli ATCC 25922 ≤2,50E-12 ≤2,50E-12

E. coli 3083559 ≤8,90E-11 ≤8,90E-11

K. pneumoniae 3083832 ≤4,16E-10 ≤4,16E-10

K. pneumoniae 3083583 ≤1,38E-11 ≤1,38E-11

P. aeruginosa ATCC 27853 ≤2,61E-12 ≤2,61E-12

P. aeruginosa 3083655 ≤2,68E-12 ≤2,68E-12

A. baumannii 3083835 ≤2,65E-12 ≤2,65E-12

A. baumannii 3083684 ≤4,80E-10 ≤4,80E-10

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NBS plates- MHB only

Compound ID

GN_01E.coli

ATCC 25922

GN_03K. pneumoniaeATCC 700603

GN_04K. pneumoniae

ATCC 13883

GN_34A.baumanniiATCC 19606

GN_42P.aeruginosaATCC 27853

GN_43P.aeruginosaPolymixin R

GN_44 E.coli

ATCC 10536

GN_45K. pneumoniae

BAA_2146

MIC [μg/mL]

Colistin MCC_000094B ≤0.03 ≤0.03 ≤0.03 0.03/0.06 1/2 32/64 0.03/0.125 0.06

Ciprofloxacin MCC_000166 ≤0.03 0.25 ≤0.03 0.5/1 2 0.25/0.5 32/64 >64

AA139 0.06 0.5 0.125/0.25 0.125 0.25/0.5 2 0.125 1/2

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 0.5/0.25 0.125

Ciprofloxacin MCC_000166 ≤0.03 2 0.5 >64 1 1 2/1 >64

AA139 0.125/0.06 0.125 0.5/0.25 2 0.5 16/8 0.5/0.25 2

8x MIC increase

Decrease in MIC

Limited effect of mucin (Survanta) on in vitro

efficacy

University of Queensland 2013

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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%)

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Confidential 14Euprotec 2013

PK/PD dose fractionation study shows that Cmax drives the efficacy of

Arenicin (NZ17230)(5mg/kg over 3 days seems to exert maximal effect)

Q36

h

Q18

h

Q12

h

Q8h

Pre-Treat-ment

NZ17230 - 3mg/kg

NZ17230 - 3mg/kg

NZ17230 - 3mg/kg

NZ17230 - 3mg/kg

1.00E-01

1.00E+00

1.00E+01

1.00E+02

1.00E+03

1.00E+04

1.00E+05

1.00E+06

1.00E+07

Tissue burdens following infection with E. coli UT189

KidneyBladderUrine

CFU/

mL

hom

ogen

ate

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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

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Euprotec 2013

ED50 for AA139 in the bladder

Excellent efficacy in UTI

E. coli K. pneumonia

log10 [AA139] mg/kg

log1

0 cf

u/g

blad

der

-1.0 -0.5 0.0 0.5 1.0 1.52

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4

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ED50 1.7 mg/kg

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Very good activity of Arenicin against K. pneumonia in a

neutropenic pneumonia model following aerosol admin

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Klebsiella Pneumonia NCTC13442

Variant log reduction MICAA139 -3.89 1

Colistin -1.75 1Euprotec 2013

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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

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Confidential

Indications Meropenem Colistin ArenicinPneumonia +++ +++ +++Complicated urinary tract infections +++ +++ +++Coverage

XDR E.coli ++ +++ +++XDR P.aeruginosa ++ +++ +++XDR A.baumannii + +++ +++KPC K.pneumonia - +++ +++Colistin G- Bacteria - - +++Administration

Oral no no noIV yes yes yesIT no yes yesAdverse events

Renal/Hepatic (yes) yes (no)Neurological no yes noHypersensitivity yes yes yesMiscellaneous

Bactericidal yes yes yes

Product profiles of Meropenem, Colistin and Arenicin

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