Smart Science for Serious Disease Company Overview March 2011

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Transcript Smart Science for Serious Disease Company Overview March 2011

Smart Science
for Serious Disease
Company Overview
March 2011
1
Board and Management
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John Beadle: CEO
GSK, Pfizer, PowderJect, PowderMed
Michael Moore: Chairman
Cantab, Xenova, Piramed, Roche
Charles Swingland: NED
PowderJect, Zeneus, Circassia
Phil L'Huillier: NED
Cancer Research Technology
Simon Kerr: Investor NED
Imperial Innovations
Maina Bhaman: Investor NED
Imperial Innovations
Mark Payton: Investor NED
Mercia Fund
Scientific Advisory Board
– Professor Stefan Anker
Professor of Applied Cachexia Research, Charité Medical
School, Berlin. Founding President of the Society for
Cachexia and Wasting Disorders.
– Professor Andrew Coats
Norwich Research Park Professor at Large, University of
East Anglia and Honorary Professor of Medicine,
University of Sydney, Australia.
– Professor Len Seymour
Chair of Gene Medicine and Head of Department of
Clinical Pharmacology, University of Oxford. President of
the British Society for Gene and Stem Cell Therapy.
– Dr Kerry Fisher
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Lecturer, Oxford University. Young Investigator of the
Year in 2009 for the European Society for Gene and Cell
Therapy.
Psioxus pipeline
MT102
Preclinical
Phase II
ColoAd1
Research
Preclinical
Phase I/IIa
Phase IIb
PolySTAR
Research
Preclinical
Phase I/IIa
PolyMAP
Research
Preclinical
Phase I/IIa
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MT-102
ANABOLIC / CATABOLIC
TRANSFORMING AGENT (ACTA)
Cachexia and sarcopenia
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MT-102:
Finding unique products that can
block the catabolic cycle
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MT-102:
Anabolic / Catabolic Transforming Agent (ACTA)
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MT-102:
Anabolic / Catabolic Transforming Agent (ACTA)
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MT102
Yoshida Rat Hepatoma Model
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MT-102
Reverses weight loss
40
**
*
20
g
0
-20
***
-40
**
**
*
-60
placebo
0.5 2
MT-100
Sham: + 59.7±2.1 g
10
1
MT-101
0.3 3
MT-102
ANOVA: p<0.0001
MT-100 and MT-101 are early research compounds now superseded by MT-102,
but data is presented here for comparison purposes
Myotec’s Lead
Compound
MT-102
Enhances survival
100
Percent survival
80
MT-102 3 mg
= Myotec’s Lead Compound
40
placebo
20
imida 10 mg
= Vitor™ in Phase III with Ark Therapeutics
0
0
11
2
4
6
8
Time
10
12
14
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MT-102
Clinical Trial
• A multicentre, randomised, double-blind,
placebo-controlled clinical study
• 132 patients
• Subjects with cachexia related to stage III and IV
– non-small cell lung cancer
– colorectal cancer
• Dose-finding phase II study with 3 parallel
groups:
– 10mg MT-102 two times per day
– 2.5mg MT-102 two times per day
– Placebo
• Over a sixteen week period
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ColoAd1
A POTENT AND HIGHLY
SELECTIVE ONCOLYTIC VIRUS
Colorectal and hepatocellular
carcinoma
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ColoAd1:
Evolved oncolytic virus
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ColoAd1
Selectively destroys cancer cells
Cell killing is determined
by the MTS assay and
the number of particles
required to kill 50% of the
cells is shown (IC50). A
smaller number indicates
that cells are more
sensitive.
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ColoAd1
Selectively destroys cancer cells
Irinotecan
ColoAd1
120
120
HUVEx(normal)
>2100
Cell viability %
Cell viability %
HepG2
>2100
x (cancer)
100
100
80
60
>1200 x
40
80
60
n.s.
40
20
20
HUVEx(normal)
>2100
HepG2
>2100
x (cancer)
0
0.001
0
0.01
0.1
1
10
ColoAd1 particles per cell
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100
1000
0.001
0.01
0.1
1
10
100
1000
Irinotecan mM
Differential killing activity of ColoAd1 on normal and tumour cells. Human hepatoma
cancer cells and normal human endothelia cells (HUVE) were exposed to a range of
concentrations of either ColoAd1 or Irinotecan. After 5 days the number of cells remaining
viable was determined using the MTS assay. The differential IC50 or ‘therapeutic index’ for
ColoAd1 was over 1200 fold while killing with irinoitecn was not appreciably different.
ColoAd1
No treatment
cisplatin
ColoAd1
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Cancer cells (A549)
Fibroblasts (Wi38)
0
10
20
30
ColoAd1
40
50
60
70
Days
In vivo treatment of orthotopic ovarian cancer
Survival Curve SKOV-LUC i.p. study
2.5
120
a
100
*
Percent survival
Tumour burden (g)
2
b
1.5
1
0.5
80
**
PBS
ONYX
Ad11
Colo
OvAd1 A
OvAd1 B
OvAd2
60
40
20
0
0
PBS ONYX Colo
0
10
20
30
40
50
60
70
70
Days of mice. After 5, 7 and 9 days
SKOV3 cells were seeded into the peritoneal compartment
mice were administered 1x1010 virus particles of ColoAd1 or ONYX-015 i.p in 100ul of
saline.
a. In the first study, animals were sacrificed after 18 days when the control groups showed
signs of high cancer burden. Residual cancer burden was determined by quantitative
PCR
b. In a second study mice were left to determine survival.
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N=7 Significance determined by t-test and log rank test.
ColoAd1
In vivo treatment of orthotopic metastatic
colorectal cancer
*
Serum CEA level
(ng/mL; Mean ± SEM)
1.01.00
250
*
0.80.80
0.60.60
0.40.40
200
150
100
50
0.20.20
0.00.00
Serum CEA level
*
300
300
300
CEA levels
Serum(ng/mL;
ng/ml
Mean ± SEM)
1.21.20
(grams, Mean ± SEM)
burden day
tumourweight
RemainingTumor
1.40
2
ColoAd1
3
Ad11p
4
ONYX-015
n=10
250
250
Significance was
determined by MannWhitney analysis,
200
200
150
150
100
100
Cancer burden analysis
was performed blinded.
*
50
50
*
*
Data taken from Khun
**et al 2008.*
00
0
1
Buffer
*
Buffer
ColoAd1CJ132
Buffer
ColoAd1CJ132
ColoAd1, low
ColoAd1,
ColoAd1,
low
middle
ColoAd1,
ColoAd1,
high
middle
ColoAd1, high
HT-29 colon cancer cells were seeded into the livers of nude mice. After hepatic cancers were
established, ColoAd1, wild type Ad11 or ONYX-015 were administered by tail vein injection.
12 days post infection mice were sacrificed and regions of remaining metastatic disease were
removed and weighed (figure a). In addition to cancer burden analysis, serum CEA was
measured as an indicator of viable cancer load (figure b). In this second study, activity of
ColoAd1 was compared against a non-replicating virus control (ColoAd1D) to demonstrate the
importance of replication.
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ColoAd1
Excellent competitive profile
• Highly selective for cancer cells
• High anticancer potency
• Potential for intravascular delivery
• Killing by necrosis
• Overcomes drug resistance
• Kills cancer stem cells
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PolySTAR
ANTIBODY RESISTANT
“STEALTHED” VIRAL VECTORS
Vaccines and gene therapy
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PolySTAR
Antibody-resistant ‘stealthed’ viruses
+
Ad5 virus
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Multivalent
Hydrophilic
Polymers
PolySTAR
Vector
PolySTAR
Pre-immune mice: luciferase expression
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PolySTAR
Targeting to Dendritic Cells: expression
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PolySTAR
Targeting to Dendritic Cells: stimulating PBMCs
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PolyMAP
HIGHLY POTENT SYNTHETIC
TOLL LIKE RECEPTOR ADJUVANTS
Vaccines and cancer
immunotherapy
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PolyMAP
Polymerised multivalent synthetic adjuvants
• Synthetic lipopeptides designed to mimic bacteria cell
wall components.
• Stimulating TLR 2 / 1, they have been developed as
adjuvants for peptide vaccines.
Synthetic TLR ligand
+
Inert
polymer
PolyMAP
• Linking synthetic adjuvants together provides a more
natural multiple-display pattern, equivalent to the
fragments of bacteria cell walls.
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PolyMAP
Mechanism of action
polymer
adjuvant
Cooperative
multivalent
interaction
Cross-link receptor
Signal transduction
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•
•
•
•
Increased affinity (avidity)
Enhanced receptor clustering and cross-linking
Improved adjuvant solubility
Improved adjuvant localisation
PolyMAP
IL-8 stimulation in BM derived dendritic cells
50ng/ml of polymer-display TLR ligand produces 5x greater IL8 expression relative to 50ng/ml free TLR ligand alone.
• But the TLR ligand represents only 5%
of the mass of the polymer conjugate
(95% polymer)
• So the 5 fold improvement in activity
is achieved with 20 fold less adjuvant specific activity of TLR ligand is
improved 100 fold
Note that polymer alone
is non-immunogenic
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PolyMAP
NF-kB simulation in macrophages
• 100 ng/ml of polymer-display-TLR ligand produces 25x
greater NF-kB expression relative to free TLR ligand alone
• PolyMAP is equivalent to 100ng/ml LPS
• But: Pam3Cys represents
only 4 % of the mass of the
polymer conjugate
• So: specific activity of
Pam3Cys is improved 600
fold
• And: 4ng of polymerised
Pam3Cys is equivalent to
100ng/ml LPS
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PolyMAP
Adjuvanting ova in mice
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PolyMAP
Adjuvanting ova in mice
But: total weights are used and the polymer conjugates contain only 4% TLR ligand
So: 40ug or 2ug of PolyMAP equals 1.6ug and 0.08ug TLR ligand respectively
And: both are better than 40ug pure TLR ligand without polymer
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PolyMAP
As a direct cancer immunotherapeutic
B16 growth rates with TLR ligand or PolyMAP given simultaneously with
tumour cells (day 0) or 10 days after implantation (day 10).
But:
TLR ligand represents only
4% of the mass of the
polymer conjugate
So:
Potency of the TLR ligand
is increased much more
than 20 fold through
polymerisation
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Smart Science
for Serious Disease
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