Transcript E. Coli - Adenium Biotech

Developing novel antimicrobials against ”difficult to treat” multi drug resistant bacteria
Presentation at BioEquity, Stockholm, May 2013
Confidential
Summary – Adenium Biotech
• A spin-out from Novozymes, founded in 2011, strong VC syndicate
• Management team with extensive experience, industry experienced
Board of Directors and strong Scientific Advisory Board of KOL´s
• ”First-in-class” Arenicin compounds with potent and selective
activity against multi-drug resistant Gram-negative bacteria
- Selection of clinical candidate/initiation of tox/safety in October 2013
- ”First in man” by end of 2014
• Funding requirement:
- USD 10 mio to progress through phase I
- USD 25 mio to progress through clinical ”proof of concept” in phase II
Confidential
2
Adenium Biotech ApS
•
Management:
- Peter Nordkild, MD, CEO, ex
Novo Nordisk, Ferring, Egalet,
ARTS Biologics
- Søren Neve, PhD, project dir,
ex Lundbeck, Novozymes
•
Board of Directors:
- Khalid Islam, PhD, ex Arpida, chairman
- Anker Lundmose, MD, ex Novo Nordisk,
OSI Pharmaceuticals
- Andreas Segerros, MSc, MBA, Sunstone
Capital
- Stephan Christgau, PhD, Novo Seeds
- Casper Tind Hansen, MSc, CEO Pcovery
- Ejner Bech Jensen, MSc, VP R&D
Novozymes A/S
•
Investors:
- Novo Seeds
- Sunstone Capital
•
Scientific advisory board:
- Prof Brad Spellberg, US
- Prof David Livermore, UK
- Dr Bruce Montgomery, US
- Dr Frank Fildes, UK
- Prof Matt Cooper, AUS
Confidential
3
Arenicin selection process.
Adenium benefits from extensive AMP know how
> 500 organisms screened for
antimicrobial activity
Several G+ but
only one Gidentified
~40 AMP’s identified
Confidential
4
Medical need for broad spectrum
Gram-negative antimicrobial
• Bacteria are rapidly becoming resistant to known antibiotics
- 160.000 patients with nosocomial XDR Gram-negative
infections in 2011 in USA alone
- Carbapenem resistant Klebsiella increased from < 5 % to
29.6% in Italy over 5 years
• Increasing resistance even to last and toxic resorts e.g. Colistin
• GAIN legislation approved to grant priority review, fast track
status and extend market exclusivity period with 5 years
• GAIN pathogens: Acinetobacter, Klebsiella, Pseudomonas and
E. Coli
Confidential
5
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
Confidential
6
Arenicin: Unique MoA and broad
spectrum Gram-negative activity
• Arenicin is bactericidal with a novel, dual mode of action
– Bacterial membrane penetration
– Protein synthesis inhibition
• Selective and specific - no hemolytic or cytotoxic activity in
mammalian cells
• Very low spontaneous mutational frequency and resistance
• Broad spectrum activities against a wide range of XDR Gramnegative pathogens
• Wide therapeutic window. 50 – 100 fold difference between
effective dose and MTD in vivo
• 21 AA peptide synthesized by standard solid phase synthesis
Confidential
7
Arenicin and the cell membrane -MoA
TEM of P.aeruginosa after incubation with AA143
Extracellular ATP after 10 min
Fold change
25
20
Ar
15
col
10
pip
5
0
0
16
64
256
x MIC
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. yaxis is fold change relative to untreated and x-axis is fold
MIC applied.
P. aeruginosa incubated with 32 μg/mL AA143. Red
arrow shows the membrane disruption. Blue arrow
shows release of the cytoplasm.
Confidential
8
Arenicin interferes with the
phospholipid homeostasis
• MlaC is a periplasmic binding protein
maintaining phospholipid homeostasis
of the dual cell membrane
• Whole genome sequencing of E. Coli
shows only one single L11R amino acid
mutation in MlaC correlating well with
the very low spontaneous mutational
frequency
Confidential
9
Arenicin shows low potential for
resistance development
Resistance Frequency
(4 X MIC)
Organism
Isolate ID
E. coli
ATCC 25922
K. pneumoniae
3083583
P. aeruginosa
ATCC 27853
A. baumannii
3083835
Confidential
AA139
AA230
≤ 2,50E-12
≤ 2,50E-12
≤ 1,38E-11
≤ 1,38E-11
≤ 2,61E-12
≤ 2,61E-12
≤ 2,65E-12
≤ 2,65E-12
10
Arenicin is selective and specific for
bacteria with low hemolytic and
cytotoxic activity
wt
Confidential
11
Arenicin shows favorable efficacy
compared to current treatment options
MIC90 determinations (MDR strains)
# strains
AA139
AA230
Ceftazidime Ciprofloxacin
N=325
Colistin
Gentamicin Meropenem Tigecycline
MIC (µg/ml)
E.coli
N=55
1
0.5
>32
>4
0.25
>32
4
0.5
K.pneumonia
N=75
4
4
>32
>4
8
>32
>16
4
P.aeruginosa
N=75
8
2
>32
>4
2
>32
>16
>8
A.baumanii
N=120
2
2
>32
>4
8
>32
>16
4
Confidential
12
Arenicin shows good activity in animal
models of UTI and Pneumonia
•
Arenicin (AA143) shows good
efficacy in the UTI model with
ED50 at 1.15 mg/kg in the bladder
•
Arenicin (AA143) shows good
efficacy in the Pneumonia model
Confidential
13
Arenicin is well tolerated with a
wide therapeutic window
• Favorable MTD in mini-pigs and mice at 30-50 mg/kg
• No observed adverse effect level (NOAEL) at 30 mg/kg
• Therapeutic window (NOAEL/ED50 bladder) of 75
• Three times longer half-life than Meropenem in mini-pigs
• Well distributed with a high volume of distribution of 900 ml
Confidential
14
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
-
-
+++
Oral
no
no
no
IV
yes
yes
yes
IT
no
yes
?
(yes)
yes
(yes)
Neurological
no
yes
no
Hypersensitivity
yes
yes
yes
Bactericidal
yes
yes
yes
Administration
Renal/Hepatic
Confidential
15
Milestone plan
• In vivo efficacy against key pathogens Pseudomonas,
Acinetobacter and Klebsiella in pneumonia
• Two leads identified for lead optimization
• Clinical candidate selection
• IND enabling tox/safety completed
• IND filing
• First in man initiation
• Initiation of clinical ”Proof of Concept” (phase II)
• Completion of clinical PoC
Confidential
Completed
Completed
Oct 2013
Q4 2014
Q4 2014
Q1 2015
Q2 2016
Q2 2017
16
External activities and cost for
development of Arenicin in cUTI
Task
2013
2014
2015
2016
2017
2018
2019
Cost
MUSD
Lead candidate selection
Synthesis of 2 kg of cGMP material (Pre clin , phI)
2.0
5
Fill and finish ( phI )
0.3
3
9
Pre-clinical tox/ safety
0.5
3
CTA/IND
0.1
12
Phase I (SAD/MAD)
2.0
6
cGMP production for ph II and III
10.0
3
Fill and finish (phII, phIII)
0.7
3
SPA meeting
0.3
12
Phase II (a and b) cUTI
Phase III studies cUTI
6.0
NDA submission
Total / Year
30.0
18
6
1.0
1.8
2.1
Confidential
13.0
14.0
10.0
10.3
0.3
52.2
17
Intellectual property
Broad IP portfolio with composition of matter and method of use patents.
NZ family
WO #
Type
Description
Issued/priority
Expires
10865
WO07023163
Composition
of matter
Arenicin-3
26.08.2005
26.08.2025
11526
WO154525A1
Composition
of matter
Arenicin-3 variants
12.06.2010
12.06.2030
11704
WO070032A1
Medical use
Treatment of UTI with Arenicin-3
11.12.2009
11.12.2029
EP12166275
Medical use
Treatment of pneumonia with
Arenicin-3 variants
01.05.2012
01.05.2033
Future patents on specific variants and formulations possible.
Confidential
18
Competitive Gram-negative antibiotics with
novel MoA in development
Compound
Company
Development
Spectrum
Target
E.coli
Klebsiella
Pseudomonas
Acinetobacter
Single pathogen
ACHN975
Achaogen
PhI
LpxC inhibitor
÷
÷

÷
Pol 7080
Polyphor ltd
PhI
Membrane modulator
÷
÷

÷
BioPhage PA
BioControl
pH2
Undefines
(Virus)
÷
÷

÷
IC 43
Novartis
ph2
Immunostimulant
(Vaccine)
÷
÷

÷
KB001
Sanofi
Ph2
PcrV inhibitor
÷
÷

÷
Broad Gram-Negative
GP-4
Trius
Preclinical
GyrB/ParE




RX04
Sanofi
Preclinical
50S ribisomal subunit




SASPject™ PT3.X
Phico
Preclinical
Inactivate bacterial
DNA




Confidential
Antimicrobial deals 2009-2012
2012
2011
2011
2011
2011
2010
2009
2009
2009
2009
2009
Target company
Inhibitex, Inc.
Mpex Pharmaceuticals, Inc
Inspire Pharmaceuticals, Inc.
Adolor
Crucell N.V.
Middlebrook Pharmaceuticals
Prolysis
Targanta Therapeutics
Genelabs Techn.
Calixa
Novexel
Upfront
Clinical
Deal
Stage of
Value Total Deal
Lead
Buyer
($m) Value ($m) Product
Bristol-Myers Squibb Company
2,500
Aptalis Pharma Inc.
224
Merck
430
Cubist
190
415
Johnson & Johnson
2,274
Victory Pharma
17
17
Biota
11
11
Pre-clinical
The Medicines Company
42
100
GSK
57
57
Cubist
93
403
2
AstraZeneca
350
425
2
Confidential
20
Key Value Drivers for Investment
• Broad spectrum XDR Gram-negative first in class drug with
unique MoA and strong patent position
• Significantly increased interest in antimicrobials area with
GAIN Act/LPAD introduction
• No new MoA programs in clinical development
• Good safety and tox properties and solid in vivo PoC package
• Phase II data package to be established for USD 25 mio
• Experienced team to execute development plan
Confidential
21
Contact details
Dr Peter Nordkild
Mobile: + 45 25 47 16 46
Email: [email protected]
Website: www.
Adeniumbiotech.com
Confidential
22