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Adenium Biotech
Antimicrobial peptides with novel mode of action
Corporate presentation December 2013
• Spin-out from Novozymes, founded in 2011
• Seed investment from Novo Seeds and Sunstone Capital
• Seed company with experienced management, industry experienced
Board of Directors, and top KOL scientific advisory board
• ”First-in-Class” systemic Anti Microbial Peptide (AMP) with potent &
selective activity against multi-drug resistant Gram-negative bacteria
–
–
–
Clinical Candidate, AA139, nominated and strong back-up candidate available
Bactericidal, new MoA, 2 week tox in pigs/rodents and efficacy in vivo completed
First-in-Man Phase I studies to be initiated by end of 2014
• Clear development plan
• Funding requirement:
EUR 8 M to progress AA139 through Phase I
EUR 20 M to progress AA139 through Phase II
• Additional AMP programs targeting Gram-positive pathogens
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Adenium Biotech - Background
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Management & Team
CEO, Peter Nordkild. Biotech entrepreneur. Previously CEO of Arts Biologics and Egalet, SVP
at Ferring and Novo Nordisk
CSO, Sergio Lociuro. Previously director of Medicinal Chemistry and Int. Project Leader in
GSK, Head of Peptide Epitope Mimetics in Polyphor Ltd and Head of Research in Arpida
COO, Søren Neve. Previously project manager for the Arenicin-3 discovery activities in
Novozymes
CMC, Kim Hejnæs. Previously project director at CMC Biologics
Board of Directors
Scientific Advisory Board
Chairman, Khalid Islam, Gentium
Anker Lundemose, Bionor
Ejner Bech Jensen, Novozymes
Andreas Segerros, Sunstone
Stephan Christgau, Novo Seeds
Casper Tind Hansen, Pcovery
Dr Bruce Montgomery (USA)
Prof. Brad Spellberg (USA)
Prof. David Livermore (UK)
Prof. Matt Cooper (AUS)
Dr Frank Fildes (UK)
Tim Joslin, Defined Health. Commercial assessment
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Adenium Biotech - Key People
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• Resistance is increasing rapidly
• Resistance is a high priority with US and EU authorities
• Even Colistin, invented in the fifties and abandoned in the sixties due to neuroand nephrotoxicity, is increasingly used but resistance is growing
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Bacterial Resistance An escalating problem calling for new MoA antibiotics
Carbapenem resistant enterobacteria
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• Most potent anti Gram-negative AMP identified by Novozymes
through screening effort comprising more than 500 organisms
• Arenicin-3 is a 21 AA peptide from the lugworm Arenicola marina
• New and dual MoA
• Novozymes has tested ≈ 250.000 Arenicin variants
• Adenium has subjected the 10 best to extensive characterization/
lead optimization and selected AA139 as the clinical candidate
• GMP manufacture initiated October 2013
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Arenicin Program
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ESKAPE pathogens
Enterobacter
Staphylococcus
Adenium Targets Gram neg GAIN act pathogens
Klebsiella
Acinetobacter
Pseudomonas
E coli
GAIN legislation from 2012 grants priority review, fast track status and extend
market exclusivity period with 5 years
E coli
Klebsiella
Pseudomonas
Adenium Lead Indication
Urinary Tract Infection (UTI)
Pneumonia (HAP/VAP)
Intra Abdominal Infection (IAI)
Acinetobacter
Possible 2’ Indications
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Arenicin Program Targets Unmet Medical Need
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Novel mode of action
Bactericidal
Selective and specific
Low frequency of resistance
Active against GAIN pathogens
Wide therapeutic window
Drugable
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Target Product Profile for multidrug resistant broad
spectrum Gram-negative antibiotic
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Arenicin has a completely novel MoA:
Distortion of phospholipid synthesis by
interaction with MlaC
Arenicin also inhibits protein synthesis
through inhibition of cytosolic processes
MlaC is a periplasmic binding protein
maintaining phospholipid homeostasis
Extracellular ATP after 10 min
Fold change
25
20
15
Ar
10
col
pip
5
0
0
Frequency of resistance <10-11
16
64
x MIC
256 1024 4096
Arenicin (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 and x-axis is fold MIC applied.
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Dual Mechanisms of Action – low spontaneous mutation
frequencies
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•
•
•
•
•
Arenicin efficacy likely driven by Cmax
AA139 has highest Cmax and largest AUC of all Arenicin variants
Plasma half life of 4.3 hours
Limited effect of Survanta (mucin analogue) on activity
Protein binding 93%
MIC90 determinations (Clinical MDR isolates)
strains
AA139
Colistin
Meropenem Ceftazidime Ciprofloxacin Gentamicin Tigecycline
N=325
MIC (µg/ml)
E.coli
N=55
1
0.25
4
R
R
R
0.5
K.pneumonia
N=75
4
R
R
R
R
R
4
P.aeruginosa
N=75
8
2
R
R
R
R
ND
A.baumanii
N=120
2
R
R
R
R
R
4
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Arenicin Clinical Candidate, AA139: Excellent PK properties
and efficacy against Multi Drug Resistant GAIN Pathogens
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• Mice inoculated on day -3
• Treatment, twice daily, on day 1 and 2. Sacrificed on day 3
• Bladder analyzed for bacterial load
E. coli
MIC: 0.5 µg/ml
K. pneumonia
MIC: 1µg/ml
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Arenicin Clinical Candidate, AA139: Low ED 50 against E.
Coli and K. pneumonia in UTI
Euprotec 2013
10
•
•
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Mice inoculated on day -3
Treatment, twice daily, on day 1 and 2. Sacrificed on day 3
Tissues analyzed for bacterial load
Comparison with standard of care, Meropenem
E.coli DSA443
Compound
µg/ml
AA139
0.12
Meropenem
<0.06
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Arenicin Clinical Candidate, AA139: Potent efficacy in UTI
against E coli at 5xED50 compared with Meropenem
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Mice inoculated on day 1
Treatment, 3 ml aerosol for 10 min at 2, 12, 24 hour post infection
Lung harvest at 34 hour post infection
Compared with standard of care, Colistin
Klebsiella Pneumonia NCTC13442
Compound
log reduction
MIC
AA139
-3.89
1
-1.75
1
Euprotec 2013
Colistin
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Arenicin Clinical Candidate, AA139: Excellent efficacy in
pneumonia compared with Colistin after aerosol admin.
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Good bioload reduction on par with Meropenem against E.coli
in mouse thigh model following IV dosing
Moderate bioload reduction against P.aeruginosa
in pneumonia following IV dosing
Pseudomonas aeruginosa VL-98
Variant
MIC (ug/ml)
log reduction
NZ17139
-1.12
1.0
Meropenem
-3.1
0.25
Potent bioload reduction superiour to Meropenem against E.coli
in peritoneal fluid following IV dosing
E.coli AID172
MIC (ug/ml)
NZ17139
log reduction
-0.4
Meropenem
-0.4
0.12
Variant
Good bioload reduction on par with Meropenem against E.coli
in bladder following IV dosing
E.coli AID172
E.coli DSA443
MIC (ug/ml)
Variant
NZ17139
log reduction
-3.8
0.12
Meropenem
-1.1
0.12
Variant
0.12
MIC (ug/ml)
NZ17139
log reduction
-1.6
Meropenem
-1.6
<0.06
0.12
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
AA139 shows potent effect against MDR Gram negative
bacteria in major animal models of infection
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AA139
(7 days of multiple dosing in mice and mini-pigs)
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MTD iv (mg/kg)
25
E. coli ED50 Bladder (UTI) (mg/kg)
1
MTD/ED50 Bladder
25
Protein binding
93
Histamine release and reversible proximal tubular damage only adverse event
No hERG or other cardiovascular toxicity
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Extensive Tox testing in rodents and mini pigs confirm safety
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Indications
Meropenem
Colistin
AA139
Pneumonia
+++
+++
+++
Complicated urinary tract infections
+++
+++
+++
++
+++
+++
MDR P.aeruginosa
-
+
++
MDR A.baumannii
-
-
+++
KPC K.pneumonia
-
-
++
Colistin resistant G- Bacteria
-
-
+++
Oral
no
no
no
IV
yes
yes
yes
Aerosol
no
yes
yes
(yes)
yes
(no)
Neurological
no
yes
no
Hypersensitivity
yes
yes
yes
yes
yes
yes
Coverage
MDR E.coli
Administration
Safety
Renal/Hepatic
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Product profiles of Meropenem, Colistin and Arenicin
Action
Bactericidal
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Compound
Company
Development
Spectrum
Target
E.coli
Klebsiella
Pseudomonas
Acinetobacter
Single pathogen
ACHN975
Achaogen
PhI
LpxC inhibitor
÷
÷
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Pol 7080
Polyphor ltd
PhI
Membrane modulator
÷
÷
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BioPhage PA
BioControl
Ph2
Bacteriophage
(Virus)
÷
÷
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IC 43
Intercell AG
(Novartis)
Ph2
Immunostimulant
(Vaccine)
÷
÷
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÷
KB001
KaloBios
(Sanofi)
Ph2
PcrV antibody
÷
÷
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÷
Broad Gram-Negative
AA139
Adenium
Preclinical
MlaC/protein
synthesis
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GP-4
Trius (Cubist)
Preclinical
GyrB/ParE
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RX04
Rib-X
(Sanofi)
Preclinical
50S ribosomal subunit
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SASPject™ PT3.X
Phico
Preclinical
Inactivated bacterial
DNA
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
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Very few new MoA Gram negative antibiotics –
most in clinical development targets Pseudomonas
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External activities and cost for development of
AA139 in cUTI
Tasks
2013
2014
2015
2016
2017
2018
2019
2020
Cost
MUSD
Lead candidate selection
API synthesis (20 g)
0.1
5
6
API Preclin/Phase I production (1.7 kg)
1.9
6
Pre-clinical tox/safety
1.3
3
CTA/IND
0.3
12
Phase I (SAD/MAD)
2.0
9
cGMP production for ph II and III (0.6 - 2.7 kg)
3.1
3
Fill and finish (phII, phIII)
0.7
3
SPA meeting
0.3
Phase II (a and b) cUTI
6.0
12
Phase III studies cUTI
NDA submission
Total / Year
30.0
18
0.1
2.8
2.2
3.6
5.0
17.0
15.0
6
0.3
0.3
46.0
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• The Arenicin platform provides opportunities for multiple
clinical indications:
• AA139 in other clinical indications than cUTI
(e.g. HAP/VAP, IAI)
• Other Arenicin variants for selected pathogens
(i.e. variants with high activity against e.g. MDR N.
Gonorrhoeae identified)
• The Plectasin platform provides opportunities for multiple
MDR Gram positive clinical indications:
• AP114 is very potent against C. difficile (cGMP material is
available/FIM studies to be initiated summer 2014)
• AP138 will be developed against cardio/osteo implant
infections caused by MDR S. aureus
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Additional programs target other GAIN pathogens
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Compound
Indication
Partner
Discovery
In vitro
In vivo
In vitro In vivo
AP114
MDR C. diff
AA139
MDR G- cUTI/HAP&VAP
AP138
MDR G+ implant infections
Arenicin
MDR N. gonorrhea
Development
Preclinical
I
Preclinical PhasePhase
I
DMID
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Lead program, AA139, will be advanced through phase II by midle of 2017
AP114 program will initiate phase I studies in H2 2014
AP138 program will initiate phase I studies in summer 2016
Additional Arenicin programs will be developed with external funding
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Adenium Expands AMP platform
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Development cost of EUR 6 mio for AA139 through phase I
Development cost of EUR 2 mio for AP114 through phase I
G&A cost of EUR 2 mio
Company plans to raise a minimum of EUR 10 mio in a
series A round in H1 2014
• Current investors (Sunstone Capital and Novo) will
participate in the series A round
• Plan to attract 1 – 2 additional investors to the syndicate
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Plans for series A round
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• AA139, one of very few new MoA, broad spectrum MDR
Gram-negative antibiotic
• First in class antibiotic with strong patenting through 2033
• Increasing resistance problem spurs interest in new antiinfectives
• Regulatory guidelines (e.g. GAIN act) provides additional
incentives for anti-infective development
• Recent deal activity (e.g. Cubist – acquisition of
Trius/Optimer; Roche – license of POL7080) confirms
interest in antibiotics
• Additional opportunities for AA139 in other indications
• AP114 program targets C. diff infection, a growing problem
with rapidly aging populations and a GAIN pathogen
ANTIMICROBIAL PEPTIDES WITH NOVEL MODE OF ACTION
Key Value Drivers for Investment
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