Silence is a biotechnology company developing RNAi therapeutics to treat diseases with large market potential. They have the industry's broadest siRNA clinical pipeline targeting cancers, eye diseases, acute organ injuries and more. Their proprietary AtuRNAi platform allows therapeutic intervention of previously "undrugable" targets and has treated over 300 patients safely to date. They are conducting clinical trials of their lead candidate, Atu027, which uses their AtuPLEX delivery system to target the PKN3 protein involved in tumor growth and metastasis for various cancers. Preliminary results show Atu027 has inhibited tumor growth and metastases in multiple cancer models.

1. Fight Cancer! Eine Initiative der Deutschen Biotechnologie
Delivering on the Promise of RNAi Therapeutics
Dr. Klaus Giese, Chief Scientific
Officer

2. 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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3. Outstanding potential of RNAi therapeutics
• Transforming technology
Complex of siRNA and
delivery vehicle (e.g.
• Allows therapeutic intervention of previously liposomes)
„undrugable‟ targets
siRNA/RISC
• RNA interference (RNAi) recognised by the Loss of
function
Nobel Prize in 2006
mRNA
• Proof of concept already demonstrated in man destroyed
using Silence„s technologies
mRNA Normal
• Commercial potential similar to monoclonal Protein
function
antibodies (sales 2010: US$48bn) DNA
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4. AtuRNAi: Best-in-class siRNA
therapeutics platform
• 2‟-O-Methylation offers greater stability Silence‟s AtuRNAi (siRNA)
and better tolerability
– No evidence of cytokine stimulation, activation of antisense strand
5’ 3’
Toll-Like Receptors or toxic metabolites
– Over 300 patients treated to date 3’ 5’
– 33 doses given to 1 patient over 9 months sense strand
(compassionate use) 2’-O-Methyl modifications
• Fast preclinical development
– Screening starts directly with modified siRNA • Issued patents in Europe and US
– Same scale up process for all AtuRNAi products
• Licensed to Pfizer, Novartis,
• Lower Cost of Goods compared to AstraZeneca, Quark
unmodified siRNA molecules
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5. Breakthrough delivery technologies
AtuPLEX™
Tumor blood vessels
Cancer & Metastases
Lung blood vessels
DACC
Acute lung injury/ARDS
Pulmonary Hypertension
Lung cancer
Liver
DBTC
Hepatocellular carcinoma
Ischemia Reperfusion Injury
Acute liver failure
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6. Silence„s DACC delivery system is highly
specific targeting the lung
• 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
Organ distribution after delivery of siRNA with DACC
125
siRNA [%ID/g tissue]
100
75
50
25
0
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7. 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
Organ distribution after delivery of siRNA with DBTC
• No gene expression inhibition detected in 70
other tissues 60
siRNA [%ID/g tissue]
50
40
30
20
10
0
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8. Strong validation through partnerships
Research
collaboration: $15M Option & licence Delivery
upfront and $400M AstraZeneca agreement with Delivery collaboratio
in milestones plus Novel approaches Quark: $82m in collaborati n on
royalties for 5 to delivery of siRNA Extension of both milestones plus on on AtuPLEX &
targets molecules collaborations royalties AtuPLEX DBTC
2006 2007 2008 2009 2010 2011 2012
Top 10
Pharma
AtuRNAi for diabetic
macular edema and AtuRNAi for acute
age-related macular renal failure and
degeneration; $95M in kidney transplantation Expansion of Delivery Delivery
milestones plus (and 2008, now in Ph. siRNA delivery delivery collaboration on collaboration on
royalties (now in Ph. II) I + II) collaboration collaboration DACC DBTC
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9. Industry‟s broadest siRNA therapeutics
clinical pipeline
Products Partners Target Delivery Market Pre-Clinical Phase I Phase II
Tissue / method size($m)
Organ
PF-4523655 RTP801 Naked siRNA $1bn+
Diabetic Macular - Local Delivery (potential)
Edema to the Eye
PF-4523655 RTP801 Naked siRNA $3.1bn (2010)
Age-related Macular - Local Delivery
Degeneration to the Eye
QPI-1002 P53 - Systemic Naked siRNA $4.4bn (2010)
Delivery to the
Prevention of Delayed Kidney
Graft Function
QPI-1002 P53 - Systemic Naked siRNA $1bn+
Delivery to the (potential)
Acute Kidney Injury Kidney
Atu027 PKN3 - Systemic AtuPLEX $8.2bn
Solid Tumors Delivery to (angiogenesis
Tumor mkt 2010)
Endothelium
Atu134 Systemic AtuPLEX $8.2bn
Solid Tumors Delivery to (angiogenesis
Tumor mkt 2010)
Endothelium
Atu111 Systemic DACC $1bn+
Delivery to Lung (potential)
Acute Lung Injury
Endothelium
Atu195 Systemic AtuPLEX $8.2bn
Solid Tumors Delivery to (angiogenesis
Tumor mkt 2010)
Endothelium
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Five of 13 global clinical siRNA programs use Silence’s AtuRNAi – over 300 patients treated

10. Atu027 targeting PKN3 for
RNAi mediated cancer therapy
Growth factor receptor
AtuPLEX
Delivery system to endothelial
intracellular
PI 3-K p110a PTEN tumor cells
p110b Ras
Akt-1 Myc
Hif-1
Akt-2
Lipid-based
PTB-1B PKN3 drug carrier
p53
Bcl-2 Redd1
AtuRNAi
Glucose Survival Tumor Metastases
uptake progression inhibitor
Motility
PKN3
 Key regulator during angiogenesis
and lymphangiogenesis
 Major regulator of metastasis/motility during
pathological processes
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11. Atu027: Strong preclinical efficacy data
• Atu027 „silences‟ the production of Origin Model T/C tumor T/C metastasis
PKN3 prostate PC-3 iprost 0.42 0.22
– PKN3 is a key regulator of blood and
PC-3 iprost 0.50 0.15
lymph vessel formation
LNCaP iprost 0.36 -
DU-145 s.c. 0.56 -
• Inhibition of PKN3 leads to:
PC-3 s.c. 0.62 -
– Reduced oxygen supply to tumour
– Reduced tumour growth/metastases pancreas MiaPaCa ipanc 0.55 0.24
Dan-G ipanc 0.66 -
• Efficacy of Atu027 demonstrated in L3.7pl ipanc 0.64 0.71
multiple cancer animal models V332 ipanc 0.73 -
– Data published in peer reviewed lung
Lewis Lung
0.55 -
journals i.v.
B-16V i.v. 0.46 -
• PKN3 associates with Rho family A-549 ipulm 0.84 0.34
GTPases, and preferentially with RhoC breast MDA-MB-435 0.77 0.40
(Pfizer)
MDA-MB-231 0.86 0.67
melanoma B-16V s.c. 0.59 -
colon LS 174T ihep 0.14 -
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12. Clinical Phase-I trial with “Atu027”
in oncology
“A prospective, open label, single-centre, Atu027 -
dose finding phase I study with Atu027(an siRNA formulation) Dose level Dose (mg/kg)
in subjects with advanced solid cancer - Atu027-I-01” based on the siRNA
content)
1 0.001

Patient Break Break End of Study
2 0.003

3 0.009 
Weeks -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
4 0.018 
0.036 
Months 0 1 2 3 4
5
6 0.072 
7 0.120 
8 0.180 
9 0.253

10 0.336

11 0.447
3-6 subjects per dose level
(Treatment: 4h i.v. infusion, 500 mL)
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13. 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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14. Thank You