Post on 10-May-2015
description
Fight Cancer! Eine Initiative der Deutschen Biotechnologie
Delivering on the Promise of RNAi Therapeutics
Dr. Klaus Giese, Chief Scientific
Officer
Silence today
• Industry leader in RNAi therapeutics (a new drug class)
• Strong expertise in delivering RNAi therapeutics in man
• Listed on LSE (AIM) with operations centralised
in Berlin (30 committed employees)
• Strong validation through multiple partnerships
supported by issued intellectual property (IP)
• Building a strong pipeline targeting unmet
medical needs with large commercial potential
• Developing the first blockbuster RNAi
therapeutic
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Outstanding potential of RNAi therapeutics
• Transforming technology
• Allows therapeutic intervention of previously „undrugable‟ targets
• RNA interference (RNAi) recognised by the Nobel Prize in 2006
• Proof of concept already demonstrated in man using Silence„s technologies
• Commercial potential similar to monoclonal antibodies (sales 2010: US$48bn)
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mRNA Normal
function
mRNA
destroyed
siRNA/RISC
Loss of
function
DNA Protein
Complex of siRNA and
delivery vehicle (e.g.
liposomes)
AtuRNAi: Best-in-class siRNA therapeutics platform
• 2‟-O-Methylation offers greater stability
and better tolerability – No evidence of cytokine stimulation, activation of
Toll-Like Receptors or toxic metabolites
– Over 300 patients treated to date
– 33 doses given to 1 patient over 9 months
(compassionate use)
• Fast preclinical development – Screening starts directly with modified siRNA
– Same scale up process for all AtuRNAi products
• Lower Cost of Goods compared to
unmodified siRNA molecules
5’
3’
Silence‟s AtuRNAi (siRNA)
5’
3’
antisense strand
sense strand
2’-O-Methyl modifications
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• Issued patents in Europe and US
• Licensed to Pfizer, Novartis,
AstraZeneca, Quark
Breakthrough delivery technologies D
BT
C
DA
CC
Tumor blood vessels
Cancer & Metastases
Liver
Hepatocellular carcinoma
Ischemia Reperfusion Injury
Acute liver failure
Lung blood vessels
Acute lung injury/ARDS
Pulmonary Hypertension
Lung cancer
Atu
PLEX™
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Organ distribution after delivery of siRNA with DACC
Silence„s DACC delivery system is highly
specific targeting the lung
0
25
50
75
100
125
siRN
A [
%ID
/g t
issu
e]
• Novel lipid-based formulation to address lung-specific diseases (e.g. acute lung injury/ARDS/lung cancer)
• DACC delivers siRNAs primarily to the lung
• Single dose sufficient to inhibit target gene expression up to a month
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0
10
20
30
40
50
60
70
Organ distribution after delivery of siRNA with DBTC
Silence„s DBTC delivery system is highly
specific to liver
• Proprietary lipid-based formulation to address liver-specific diseases (e.g. hepatocellular carcinoma)
• DBTC delivers specifically to the liver
• Single dose inhibits target gene expression in the liver up to a week
• No gene expression inhibition detected in other tissues
si
RN
A [
%ID
/g t
issu
e]
7
2006 2007 2008 2009 2010 2011 2012
Delivery
collaboratio
n on
AtuPLEX &
DBTC
Strong validation through partnerships
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AtuRNAi for diabetic
macular edema and
age-related macular
degeneration; $95M in
milestones plus
royalties (now in Ph. II)
AtuRNAi for acute
renal failure and
kidney transplantation
(and 2008, now in Ph.
I + II) siRNA delivery
collaboration
Expansion of
delivery
collaboration
Delivery
collaboration on
DACC
Research
collaboration: $15M
upfront and $400M
in milestones plus
royalties for 5
targets
AstraZeneca
Novel approaches
to delivery of siRNA
molecules
Option & licence
agreement with
Quark: $82m in
milestones plus
royalties
Extension of both
collaborations
Delivery
collaborati
on on
AtuPLEX
Top 10
Pharma
Delivery
collaboration on
DBTC
Products Partners Target
Tissue /
Organ
Delivery
method
Market
size($m)
Pre-Clinical Phase I Phase II
PF-4523655 Diabetic Macular
Edema
RTP801
- Local Delivery
to the Eye
Naked siRNA $1bn+
(potential)
PF-4523655
Age-related Macular Degeneration
RTP801
- Local Delivery
to the Eye
Naked siRNA $3.1bn (2010)
QPI-1002
Prevention of Delayed Graft Function
P53 - Systemic Delivery to the Kidney
Naked siRNA
$4.4bn (2010)
QPI-1002
Acute Kidney Injury
P53 - Systemic Delivery to the Kidney
Naked siRNA $1bn+ (potential)
Atu027 Solid Tumors
PKN3 - Systemic
Delivery to
Tumor
Endothelium
AtuPLEX $8.2bn
(angiogenesis
mkt 2010)
Atu134 Solid Tumors
Systemic
Delivery to
Tumor
Endothelium
AtuPLEX $8.2bn
(angiogenesis
mkt 2010)
Atu111 Acute Lung Injury
Systemic
Delivery to Lung
Endothelium
DACC $1bn+ (potential)
Atu195 Solid Tumors
Systemic
Delivery to
Tumor
Endothelium
AtuPLEX $8.2bn
(angiogenesis
mkt 2010)
Industry‟s broadest siRNA therapeutics clinical pipeline
Five of 13 global clinical siRNA programs use Silence’s AtuRNAi – over 300 patients treated 9
PTEN
Growth factor receptor
intracellular
Glucose uptake
Tumor progression
Metastases
Motility
Survival
Akt-2
Akt-1
Bcl-2 p53
Redd1
Hif-1
PTB-1B PKN3
Ras
Myc
p110a PI 3-K
Atu027 targeting PKN3 for
RNAi mediated cancer therapy
PKN3 Key regulator during angiogenesis
and lymphangiogenesis
Major regulator of metastasis/motility during
pathological processes
p110b
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AtuPLEX Delivery system to endothelial
tumor cells
Lipid-based
drug carrier
AtuRNAi
inhibitor
Atu027: Strong preclinical efficacy data
• Atu027 „silences‟ the production of PKN3
– PKN3 is a key regulator of blood and lymph vessel formation
• Inhibition of PKN3 leads to:
– Reduced oxygen supply to tumour
– Reduced tumour growth/metastases
• Efficacy of Atu027 demonstrated in multiple cancer animal models
– Data published in peer reviewed journals
• PKN3 associates with Rho family GTPases, and preferentially with RhoC (Pfizer)
Origin Model T/C tumor T/C metastasis
prostate PC-3 iprost 0.42 0.22
PC-3 iprost 0.50 0.15
LNCaP iprost 0.36 -
DU-145 s.c. 0.56 -
PC-3 s.c. 0.62 -
pancreas MiaPaCa ipanc 0.55 0.24
Dan-G ipanc 0.66 -
L3.7pl ipanc 0.64 0.71
V332 ipanc 0.73 -
lung Lewis Lung
i.v. 0.55 -
B-16V i.v. 0.46 -
A-549 ipulm 0.84 0.34
breast MDA-MB-435 0.77 0.40
MDA-MB-231 0.86 0.67
melanoma B-16V s.c. 0.59 -
colon LS 174T ihep 0.14 -
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Dose level
Atu027 -
Dose (mg/kg) based on the siRNA
content)
1 0.001
2 0.003
3 0.009
4 0.018
5 0.036
6 0.072
7 0.120
8 0.180
9 0.253
10 0.336
11 0.447
Clinical Phase-I trial with “Atu027”
in oncology
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 -2 -1
0 1 2 3 4 Months
Weeks
Break Break End of Study Patient
“A prospective, open label, single-centre,
dose finding phase I study with Atu027(an siRNA formulation)
in subjects with advanced solid cancer - Atu027-I-01”
3-6 subjects per dose level
(Treatment: 4h i.v. infusion, 500 mL)
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Atu027 Phase I summary and
outlook
• Atu027 is positioned to treat vascularised tumours
• Eleven patients confirmed with stable disease
• Potential biomarkers identified
• Final data expected by mid–2012
• Current discussions for phase II - Atu027 in combination with standard of care to treat solid
tumors
- Mono-therapy (salvage therapy) in recurrent Glioblastoma
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Thank You