Confidential
Adenium Biotech
Management: - Peter Nordkild, MD, CEO, ex Novo Nordisk, Ferring, Egalet - Søren Neve, PhD, project director, ex Lundbeck, Novozymes
Board of Directors: - Khalid Islam, PhD, ex Arpida, chairman - Stephan Christgau, PhD, Novo A/S - Andreas Segerros, Sunstone Capital - Anker Lundemose, MD, ex Novo Nordisk, OSI Pharmaceuticals - Ejner Bech Jensen, MSc, VP R&D Novozymes A/S - Casper Tind Hansen, MSc, Novo A/S
Current Investor: - Novo A/S Special advisor: professor Brad Spellberg
Confidential
Bad Bugs – No Drugs (IDSA, 2004)
• The total US market of hospital acquired infections was in 2006 estimated at USD 7.9 billion.
• 65% of hospital acquired infections are caused by Gram-negative bacteria (Clin Infect Dis 2005;41:848–854)
Resistance
Confidential
ESKAPE pathogens
• Enterococcus faecium• Staphylococcus aureus Klebsiella species Acinetobacter baumannii Pseudomonas aeruginosa Enterobacter
E.coli E. aerogenes E. cloacae
Confidential
Competitive Gram-negative antibiotics in development
Company Development Compound
Spectrum
E.coli Klebsiella Pseudomonas Acinetobacter
Avibactam (Ceftatroline)
Forest/AstraZeneca/Novexel
PhII/III Cephalosporin
CAZ104 AstraZeneca/Novexel
PhII β-lactamase inhibitor () ()
TP434 Tetraphase PhII Fluorocycline ÷ GSK 2251052 Anacor/GSK PhII
On holdNovel ÷
Plazomicin(ACH490)
Achaogen PhI Aminoglycoside ÷ ÷BAl30072 Basilea
PharmaceuticaPhI β-lactam antibiotic
MC1 Pfizer Preclinical β-lactam antibiotic ÷RX04 Sanofi Preclinical Novel RecA inhibitors Synerca Discovery Novel ? ? ? ?ME1070 Meiji Seika Discovery β-lactamase
inhibitor ?
Confidential
Arenicin-3 NZ17000
• Isolated from lugworm (Arenicola marina)• 21 amino acids• Very stable beta-hairpin structure• MW 2.613 kDa• pI ~ 11.27
Confidential
Arenicin program highlights
• Novel mode of action, no cross resistance to existing antibiotics• Bactericidal on broad range of multidrug resistant Gram-negative
bacteria• Wide therapeutic window established in mice and pigs • No novel bactericidal Gram-negative antibiotics in clinical
development• Strong lead/back up product candidates• Stable IV formulations• Strong IP (2025-2030)• Addresses significant unmet Gram-negative clinical need• Large, growing and non-generic hospital market of USD 8 billion• Hospital and primarily ICU based specialist target group requiring
small sales force
Confidential
Wildtype has broad spectrum in vitro activity against clinical
isolatesMinimal inhibitory concentration (µg/ml) for NZ17000
Bacterial Strains # 0.063 0.125 0.25 0.5 1 2 4 8 16 32
Pseudomonas 24 6 7 7 3 1
Stenotrophomonas 8 3 1 2 2
Citrobacter 7 2 5
Enterobacter 5 1 3 1
Escherichia coli 24 1 11 9 3 1
Hafnia alvei 1 1
Klebsiella 9 4 4 1
Proteus mirabilis 3 1 1 1
Salmonella enterica 8 2 6
Serratia marcescens 2 2
Shigella 2 2
Achromobacter 3 2 1
Acinetobacter 4 2 1
Aeromonas 10 2 2 4 2
Alcaligenes 5 2 2 1
Confidential
MIC and protein binding of selected variants
E.coli E.coli E. coli Klebsiella Enterobacter Pseudomonas
Pseudomonas
VibrioStenotropho
monasAcinetobacter Moraxella Neisseria % Binding
ATCC25922
ATCC27853
wt 0,25 0,5 0,5 1 1 0,5 1 2 0,5 0,5 0,5 4 99
143 0,25 0,25 0,25 4 4 2 2 8 8 4 2 16 85
211 0,5 2 0,5 8 8 4 4 16 8 4 2 >16 80
125 0,25 0,25 0,125 1 1 0,5 0,5 2 2 1 0,125 8 85
139 0,06 0,25 0,125 1 1 0,5 1 2 0,5 0,5 0,25 0,5 95
224 0,125 0,5 0,125 1 1 0,5 1 2 2 0,5 0,25 4 96
228 0,25 0,5 0,125 1 2 0,5 1 2 1 0,5 0,12 4 85
230 0,125 0,5 0,125 2 1 0,5 0,5 2 1 0,25 0,25 8 97
Confidential
MoA - localization of Arenicin
A. E. coli exposed for 30 min to NZ17000 and stained with TRITC. Treatment with NZ17000 results in influx of TRITC into the E. coli
B. E. coli exposed for 30 min with TRITC labelled NZ17000. Clusters of NZ17000 were localized in the bacterial membrane
0 16 64 256 1024 40960
5
10
15
20
25
Arcolpip
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.
• Perturbs the membrane potential increasing the permeability of the bacterial membrane.
• Inhibits the protein synthesis.
Confidential
Wildtype time to kill vs E.coli and Pseudomonas
Time kill kinetics for Escherichia coli ATCC25922NZ17000 in ca-Müller Hinton broth
0 30 60 90 120 150 180101
102
103
104
105
106
107
108
109
Growth control
10 x MIC Gentamicin (5µg/ml)10 x MIC Arenicin-3 (5µg/ml)
Time (minutes)
CFU
/ml
NZ17000 Time killing kinetics forPseudomonas aeruginosa ATCC27853
0 30 60 90 120 150 180101
102
103
104
105
106
107
108
Growth Control0.25 x MIC NZ17000 ( 0.125µg/ml)2 x MIC NZ17000 (1µg/ml)10 x MIC NZ17000 (5µg/ml)
Time (minutes)
CFU/
ml o
f Pse
udom
onas
Confidential
Effect of NZ17143 in a 24 hour mouse pneumonia model against Klebsiella pneumoniae (ATCC 43816)
Confidential
Efficacy of NZ17143/NZ17211 against MDR E. coli in the murine Urinary Tract Infection model
2
3
4
5
6
7
8Urine day 2 post infection
Lo
g10
CF
U/m
l
vehic
le
NZ1714
3 12
.5 m
g/kg
NZ1721
1 20
mg/k
g
Mer
openem
40
mg/k
g
2
3
4
5
6
7
8 Bladder day 3 post infectionL
og
10
CF
U/m
l
vehic
le
NZ1714
3 12
.5 m
g/kg
NZ1721
1 20
mg/k
g
Mer
openem
40
mg/k
g
1
2
3
4 Kidneys day 3 post infection
Lo
g10
CF
U/m
l
Kidney 3 days post infectionBladder 3 days post infectionUrine 2 day post infection
Confidential
Dose response of NZ17211 in the UTI mouse model
ED50 ~0.2 mg/kg in urine and the bladder
Confidential
Pharmacokinetic properties after IV administration
Arenicin-3 variant Protein binding(%)
T½
(min)AUC
(min*ug/ml)Cmax
(ug/ml)Bioavailability(%, SC vs IV)
NZ17000 >99 130 532 7.7 12
NZ17143 85 69 324 7.5 70
NZ17211 80 60 432 9.9 60
Confidential
In vivo toxicological overview after 7 days of multiple dosing in pigs and mice
Variant NZ17000 NZ17143 NZ17211
MTD iv (mg/kg) 25 50 50
NOAEL iv (mg/kg) 10 30 40
HED (mg/kg) 9,5 28,5 38
E. coli ED50 Bladder (mg/kg) 1,8 0,4 0,2
NOAEL/ED50 Bladder 6 75 200
Protein binding 99 85 80
Confidential
Intellectual property
NZ familyWO #
Type Description Issued/priority Expires
10865WO07023163
Composition of matter
Arenicin-3 26.08.2005 26.08.2025
11526WO154525A1
Composition of matter
Arenicin-3 variants 12.06.2010 12.06.2030
11704WO070032A1
Medical use Treatment of UTI with Arenicin-3 11.12.2009 11.12.2029
Confidential
Arenicin summary• New mode of action• Spontaneous mutational frequency for E. coli is 3X10-9 and
P. aeruginosa <10-8 • Potent in vitro activity against a wide spectrum of MDR Gram-
negative bacteria• Rapidly bactericidal – MBCs ~ MICs• No cross resistance to known antibiotics• No or little inoculum effect• Favorable efficacy in experimental animal models of infection:
– Pneumonia against Klebsiella– UTI against E. coli– Septicemia against E. coli and P. aeruginosa– Thigh infections against E. coli.