Arenicin-A-novel-an-potent-anti-microbial

Report
Anti microbial peptides for the fight against multi drug resistant bacteria
Corporate presentation, February 2013
Confidential
Summary – Adenium Biotech
• New biotech company
- Spin out of Novozymes AMP program
- Strong scientific advisory board and VC syndicate
• Target XDR Gram negative bacteria
- Gram-negative platform with novel mode of action
- No novel bactericidal Gram-neg antibiotics in clinical development
• Adenium Biotech pre-clinical studies
- In vivo efficacy against XDR Klebsiella, Pseudomonas,
Acinetobacter and E. coli in several animal models
- Wide therapeutic window in mice and pigs
- Lead optimization for selection of lead product candidate in 2013
• Strong intellectual property position
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Adenium Biotech ApS
•
Management:
- Peter Nordkild, MD, CEO, ex
Novo Nordisk, Ferring, Egalet,
ARTS Biologics
- Søren Neve, PhD, project dir,
ex Lundbeck, Novozymes
•
Investors:
- Novo Seeds
- Sunstone Capital
•
•
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, Novo Ventures
- Ejner Bech Jensen, MSc, VP R&D
Novozymes A/S
Scientific advisory board:
- Prof Brad Spellberg, US
- Prof avid Livermore, UK
- Dr Bruce Montgomery, US
- Dr Frank Fildes, UK
- Prof Niels Høiby, Denmark
Confidential
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Arenicin selection process
> 500 organisms screened for
antimicrobial activity
Several G+ but
only one Gidentified !
~40 AMP’s identified
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4
Unique MoA and broad spectrum
Gram-negative activity
• Arenicin has dual mode of action and is bactericidal
– Bacterial membrane penetration
– Protein synthesis inhibition
– No haemolytic or cytotoxic activity in mammalian cells
• Broad spectrum activities against a wide range of XDR Gram
negative pathogens
• Wide therapeutic window. 50 – 200 fold difference between
effective dose and MTD in vivo
• Very low spontaneous mutational frequency and resistance
• 21 AA peptide synthesized by standard solid phase synthesis
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Arenicin-3 and the cell membrane -MoA
A. E. coli exposed for 30 min to
wt and stained with TRITC.
Treatment with wt results in
influx of TRITC into the E. coli
B. E. coli exposed for 30 min
with TRITC labelled wt.
Clusters of wt were localized
in the bacterial membrane
Extracellular ATP after 10 min
Fold change
25
20
Ar
15
col
10
pip
5
0
0
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.
16
64
256
x MIC
1024 4096
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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Low hemolytic and low cytotoxic
activity
wt
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Efficacy compared to current treatment
options. MIC90 determinations
#
strains
wt
AA139
AA143
AA230
MIC (µg/ml)
N=325
Ceftazidime
Ciprofloxacin
Colistin
Gentamicin
Meropenem
Tigecycline
MIC
(µg/ml)
CLSI
MIC
(µg/ml)
CLSI
MIC
(µg/ml)
CLSI
MIC
(µg/ml)
CLSI
MIC
(µg/ml)
CLSI
MIC
(µg/ml)
CLSI
E.coli
N=55
0.5
1
0.5
0.5
>32
R
>4
R
0.25
S
>32
R
4
S
0.5
S
K.pneumonia
N=75
4
4
16
4
>32
R
>4
R
8
R
>32
R
>16
R
4
I
P.aeruginosa
N=75
2
8
16
2
>32
R
>4
R
2
S
>32
R
>16
R
>8
R
A.baumanii
N=120
1
2
32
2
>32
R
>4
R
8
R
>32
R
>16
R
4
I
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Spontaneous mutational frequency
Resistance Frequency (4XMIC)
Organism
Isolate ID
E. coli
ATCC 25922
E. coli
3083559
K. pneumoniae
3083832
K. pneumoniae
3083583
P. aeruginosa
ATCC 27853
P. aeruginosa
3083655
A. baumannii
3083835
A. baumannii
3083684
wt
AA139
AA143
AA230
≤ 3,57E-11
≤ 2,50E-12
≤ 3,57E-11
≤ 2,50E-12
≤ 2,08E-11
≤ 8,90E-11
≤ 2,08E-11
≤ 8,90E-11
≤ 9,09E-11
≤ 4,16E-10
≤ 9,09E-11
≤ 4,16E-10
≤ 5,00E-11
≤ 1,38E-11
≤ 5,00E-11
≤ 1,38E-11
≤ 8,30E-11
≤ 2,61E-12
≤ 8,30E-11
≤ 2,61E-12
≤ 7,14E-11
≤ 2,68E-12
≤ 7,14E-11
≤ 2,68E-12
≤ 3,44E-11
≤ 2,65E-12
≤ 3,44E-11
≤ 2,65E-12
≤ 7,14E-10
≤ 4,80E-10
≤ 7,14E-10
≤ 4,80E-10
Confidential
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Klebsiella/Pseudomonas/Acinetobacter
bioload reduction
Klebsiella Pneumonia ATCC
43816
log
Variant
reduction
Pseudomonas aeruginosa
VL-98
Acinetobacter baumanii
377
Variant
log reduction
Variant
log reduction
AA143
-2,29
AA139
-1,12
AA143
-1,01
AA139
-1,89
AA230
-0,92
wt
-0,92
AA230
-1,71
AA143
-0,10
AA139
-0,18
wt
-1,59
wt
0,26
AA230
-0,04
Meropenem
-0.67
Meropenem
-2.72
Meropenem
-1.49
Mouse lung infection
Hours
0
Inoculum
2
Mouse strain : CD-1
4
Treatment
Bacteria ~108
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8
24
Evaluation of CFU in
lung
10
Dose response in the UTI mouse model
ED50 ~1.5 mg/kg in urine and ~ 1.8 mg/kg in the bladder
Mouse urinary tract infection
Mouse strain : OF-1
Days
-4
5% glucose
in drinking water
0
Inoculum
E.coli ~108
1
Treatment
BID
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Evaluation of CFU in
Urine, Bladder
And Kidney
11
Toxicological overview after 7 days of
daily dosing in mice
Variant
wt
AA139
AA143
AA230
MTD iv (mg/kg)
25
30
50
40
NOAEL iv (mg/kg)
10
-
30
-
HED (mg/kg)
9,5
N/A
28,5
N/A
E. coli ED50 Bladder
(mg/kg)
1,8
N/A
0,4
N/A
NOAEL/ED50 Bladder
6
N/A
75
N/A
Protein binding
99
95
85
97
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Comparison of kinetics in pigs
and mice
Mini pig
mg/kg
2h IV Infusion
HL_Lambda_z
Cmax
wt
AA143
AA143
18
20
38
42
Mini pig
Mouse
Mini pig
Mouse
4.8
3.4
2.2
1.9
18
27
57
54
1.0
1.3
1.5
1.3
98
77
212
120
34
20
10
6
826
102
505
895
120
208
162
324
hr
ug/ml
Cmax_D
ug/ml/mg
AUCall
hr*ug/ml
AUC_%Extrap_obs
%
Vz_obs
ml
Cl_obs
wt
ml/hr
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Development program
•
•
•
•
Selection of lead product candidate in Q3 2013
CMC and preclinical tox initiated in Q4 2013
First human dose in Q4 2014
Phase IIa initiated in 2015
– Initial registration in cUTI
– Main indication HAP/VAP
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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
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Milestone plan
•
•
•
•
•
•
•
•
•
•
•
In vivo efficacy demonstrated against Pseudomonas,
Acinetobacter and Klebsiella in pneumonia
Three leads identified for lead optimization
Bronchioalveolar lavage study
Mode of action
ED 50 in pneumonia
PK/PD in UTI
Lead candidate selection
Pre-clinical tox/safety completed
IND filing
Phase I SAD/MAD study completed
Phase IIa completed
Confidential
Completed
Completed
April 2013
May 2013
Sept 2013
Oct 2013
Oct 2013
Dec 2014
Q1 2015
Q1 2016
Q1 2017
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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.
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Key Value Drivers for Investment
• Broad spectrum XDR Gram-negative first in class drug
with unique MoA
• Significantly increased interest in anti-infectives 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 IIa data package to be established for USD 15
mio
• Experienced team to execute development plan
Confidential
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Contact details
Dr Peter Nordkild
Mobile: + 45 25 47 16 46
Email: [email protected]
Website: www.
Adeniumbiotech.com
Confidential
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