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)

3

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)

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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