Delivering on the Promise of RNAi Therapeutics
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Transcript of Delivering on the Promise of RNAi Therapeutics
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
4
• 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™
5
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)
12
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