silence therapeutics - gene silencing - corporate presentation september 2011
DESCRIPTION
This presentation outlines the history and recent developments of Silence Therapeutics, a biopharmaceutical company developing novel therapeutics based on RNA interference. Silence Therapeutics is a world leader in the discovery, development and delivery of novel RNA interference (RNAi) therapeutics for the treatment of serious diseases. With an experienced team leading pharmaceutical development, almost half of all on-going siRNA clinical trials are based on Silence technology. Find out more in the presentation or go to the website www.silence-therapeutics.comTRANSCRIPT
Corporate PresentationSeptember 2011
22
Forward-Looking Statements
The statements made in this presentation may contain certain forward-
looking comments. Actual events or results may differ from the
Company’s expectations. In addition to the matters described in the
presentation, future actions by the European Agency for Evaluation of
Medicinal Products, the U.S. Food and Drug Administration or
equivalent regulatory authorities in other countries and results of
pending or future clinical trials, as well as other risk factors outlined
from time to time in the Company’s regulatory filings, may affect
actual results achieved by the Company. The Alternative Investment
Market (AIM) has not reviewed and does not accept responsibility for
the adequacy or accuracy of this presentation.
2
Background
• Silence Therapeutics AG (formerly Atugen AG) was founded in 1998 as spin-off from RPI (later renamed to Sirna) and financed by MPM Capital, Apax and NVF
• Target discovery and validation service company using antisense and delivery technologies -> over US$20m accum. service revenues from pharma companies
• Developing delivery technologies for oligonucleotides since 1998
• First AtuRNAi patent application filed in 2002, US patent granted in Nov. 2008
• In 2005 reverse merger with SR Pharma plc (shell) listed on AIM, London
• Renamed to Silence Therapeutics plc/AG in 2007 (LSE: SLN)
• Acquired US siRNA therapeutics company Intradigm Corp. in January 2010
• To date over £50m invested in RNAi platform
• Well funded following successful £5.9m fundraising in May 2011
• Current market cap. c.£11m -> technology value of only £5m
3
4
• World leader in the discovery, development and delivery of novel RNA interference
(RNAi) therapeutics for the treatment of serious diseases− RNAi offers a unique new class of drugs that overcomes hurdles of existing drugs
• One of the sector’s most comprehensive RNAi platforms − Deliver to more target cells and tissues that anyone else (e.g. AtuPlex, DACC)
• One of the industry’s broadest RNAi clinical pipelines− Five of the 12 siRNA (& 4 of the 5 Phase II) clinical programs worldwide are based on Silence
technology
− Clinical and pre-clinical pipeline in diverse therapeutic areas – metabolic, pulmonary, vascular,
oncology
− Encouraging Phase I data on lead internal candidate Atu027 recently presented at ASCO
• Validating partnerships with leading global pharmaceutical companies− AstraZeneca, Pfizer/Quark, Novartis/Quark and Dainippon Sumitomo
• Broad intellectual property portfolio− Issued patents covering aspects of delivery, sequences and structures
Overview
5
Almost half of all ongoing siRNA clinical trials are based on Silence technology
Products Indications Partners Target Delivery Pre-
Clinical
Phase I Phase II Target Tissue /
Organ
Partn
ere
d p
rogra
ms
PF-4523655
(AtuRNAi)
Diabetic Macular
Edema
Pfizer/Quark RTP801 Naked
siRNA
Local Delivery to the
Eye
PF-4523655 (AtuRNAi)
Age-related Macular
Degen
Pfizer/Quark RTP801 Naked
siRNA
Local Delivery to the
Eye
QPI-1002 (AtuRNAi)
Prevention of Delayed
Graft Function
Novartis/
Quark
P53 Naked
siRNA
Systemic Delivery to the Kidney
QPI-1002 (AtuRNAi)
Acute Kidney Injury Novartis/
Quark
P53 Naked
siRNA
Systemic Delivery to the Kidney
Inte
rnal p
rogra
ms
Atu027
(AtuRNAi)
GI & Lung & other
cancers
Internal PKN3 AtuPLEX Systemic Delivery to
Tumor Endothelium
Atu134
(AtuRNAi)
Solid Tumors Internal AtuPLEX Systemic Delivery to
Tumor Endothelium
Atu111
(AtuRNAi)
Acute Lung Injury Internal DACC Systemic Delivery to
Lung Endothelium
Atu195
(AtuRNAi)
Solid Tumors Internal AtuPLEX Systemic Delivery to
Tumor Endothelium
Silence Product Pipeline
6
Current Partnership Overview
• AstraZeneca - $15M upfront payment with up to $400M in milestones
plus sales royalties for five targets (2007, extended 2010)
• AstraZeneca – Novel approaches to delivery of siRNA molecules (2008,
extended 2010)
• Pfizer/Quark – Phase II products for diabetic macular edema and age-
related macular degeneration; $95M in milestones plus royalties (2006)
• Novartis/Quark – Phase I/II products for acute renal failure and kidney
transplantation; $82m in milestones plus royalties (2010)
• Dainippon Sumitomo – siRNA delivery collaboration (2009, expanded
2010)
Silence’s RNAi therapeutic platform has been validated through multiple major partnerships
Commercialisation Strategy
• Out-license / co-develop internal candidates– e.g. Atu027 (in 2012), Atu111 (in 2012), Atu134 (TBD), Atu195 (TBD)
• Form new collaborative alliances with pharmaceutical partners (target-specific)– e.g. AstraZeneca and Dainippon Sumitomo
• Grant access to our proprietary technology platform (target-specific)– e.g. Quark/Pfizer and Quark/Novartis
– securing near-term non-dilutive funding
– build long-term platform value
• Collaborate with biotech partners– e.g. for co-development of novel delivery approaches
7
PF-4523655: Opthamology
• Silence licensed AtuRNAi technology to Quark in 2004
• Pfizer licensed PF-’655 in 2006 from Quark
• Milestones to Silence total $95m– next milestone c$4m on phase III start
• Phase II trial in diabetic macular oedema (DME) showed superiority over laser therapy– Phase IIb to start in 2011
• Phase II trial in age-related macular degeneration (AMD) data due in 2H11
• Low single-digit effective royalty rate on end sales
2010 Market size (AMD) $3.1bn
Potential Market size (DME) $1bn+
DME
24%
AMD
76%
Source: company reports
8
QPI-1002: Renal disease
• Silence licensed AtuRNAi technology to Quark in 2005
• Novartis signed $10m option for QPI-1002 in 2010
• Milestones to Silence of c.$82m– next milestone $3-11m on exercise of
option
• Phase II trial in prevention of delayed graft function (DGF) initiated September 2010 (results due 2012)
• Phase II trial in acute kidney injury (AKI) expected to commence 2H11
• Low single-digit effective royalty rate on end sales
2010 Market size (transplant) $4.4bn
Potential Market size (AKI) $1bn+
Neoral
19%
Myfortic
10%
Cellcept
29%
Prograf
42%
Source: company reports
9
AtuPLEX
Vascular endothelium• Cancer & Metastasis
• Inflammation
DBTC
Liver parenchyma• Hepatocellular carcinoma
• Ischemia Reperfusion Injury
• Fulminant Fibrosis
DACC
Pulmonary endothelium• Acute lung injury/ARDS
• Pulmonary Hypertension
• Infection & Inflammation
Overcoming the Delivery Challenge
10
Atu027/Atu134: Market opportunity
• Anti-angiogenic market worth $8.2bn
• Both Atu027 and Atu134 are anti-angiogenic drugs
• Atu027 is only RNAi anti-angiogenic drug in clinical development
• Atu027 will be used in the setting of highly vascularised tumours; prostate, lung, ovarian & melanoma
• Results of on-going phase I trial expected at end 2011
• Interim data to be presented at ASCO, June 2011
• Partner Atu027 in 2012 – upfront, milestones and royalties
Anti-angiogenic – works by disrupting blood supply to tumours
2010 Market size (oncology) $53bn
Chemotherapy,
19.3
Other small
molecules, 6.7
Other
antibodies, 10
Hormone
Therapies, 8.9
Anti-
angiogenics,
8.2
Source: company reports
11
Atu027 deal structure
• Plan to partner in 2012
• Partnering discussions initiated
• Typical deal structure
– Upfronts (double digit $m’s)
– Milestones (significant)
– Royalties (double digit %)
• Variations
– Global rights
– Regional rights
– Ex-US/Eu rights
– Opt-in rights
0
5
10
15
20
25
30
35
Lead Preclinical Phase I Phase II Phase III
Big Pharma alliances 2005-9
0
50
100
150
200
Upfront R&D Milestones Equity
Early stage deals 2005-9
Upfr
ont
paym
ent
($m
)Paym
ents
($m
)
Source: RECAP Deloitte
13
Atu027: Strong preclinical efficacy data
DU-146 prostate Xenograft (N = 8)
Twice weekly treatment
0 20 - 45 46 days
Atu027
Avastin
Vehicle
Atu027
VEGF-R-siRNA-lipoplex
Avastin
Atu027 + Avastin
VEGF-R-siRNA-lipoplex
+ Avastin
• 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
• Atu027 has been shown to knock-down protein and mRNA expression of PKN3 in animal models
• Impressive data led to start of Phase I trial in 2009
• Data from Cohort 6: First dose level where efficacy was predicted based on preclinical work
Of three patients treated:
– one patient showed tumour shrinkage (above)
– one patient showed stable disease at end of treatment phase
– one patient discontinued treatment for non-drug related reasons
1 week after 8th repeated treatmentBaseline (pre-treatment)
Note: vanished metastatic lesion in the left lower lobe of the lung (circle)
BEFORE AFTER
Atu027: Phase I results promising
14
0
1000
2000
3000
4000
Sucrose Luciferase CD31 control
(Atu134)T
um
or
volu
me [
mm
3]
Breast (mammary fat pad)
* p=0.003
* p=0.002 * p=0.014
Atu134: Strong preclinical efficacy data
• Atu134 has demonstrated efficacy in a variety of preclinical cancer models
– Orthotopic models
– Ectopic models
• Atu134 has demonstrated strong efficacy against primary tumour
• Targets CD31 – well validated target
• GMP manufacturing commencing
• Preclinical toxicology testing due to start early in 2012
• IND filing expected in 2012
• Plan to partner during Phase I
– target double digit royalty rate
In preclinical studies
Atu134 significantly reduced
tumour growth
15
Organ distribution after delivery of siRNA with DACC
Atu111: treatment of acute lung injury
0
25
50
75
100
125
siRN
A [
%ID
/g t
issu
e]
16
• Acute lung injury (ALI) is an area of high unmet medical need
• Significant market opportunity
– Pneumonia is 2nd highest cause of hospital admissions
– Pneumonia treatment costs $8bn/yr in US alone (mortality rate 12-30%)
– ALI principle cause of mortality
• DACC delivery system provides exquisitely selective delivery to lung (see chart)
• DACC delivery system leads to prolonged knock-down
– potential for only one dose in ALI
• Aim to partner in 2012
– target high single digit royalties
0
10
20
30
40
50
60
70
Organ distribution after delivery of siRNA with DBTC
siRN
A [
%ID
/ti
ssue]
DBTC: Targeting the Liver
no functional delivery of siRNA to spleen
no knockdown in spleen tissue. 17
• Proprietary lipid-based formulation targeting liver
• Significant market opportunities
– Liver cancer
– Ischemia reperfusion injury
– fibrosis
• DBTC delivers siRNAs primarily to liver (see chart)
• DTBC delivery system leads to persistent knock-down
– Single dose knocks down gene expression for up to 1 wk
• DTBC well tolerated
– Dosed up to 8.3mg/kg
Burn rate significantly reduced in 2H10
£000s 1H10A 2H10A 2010A
Revenue 716 1,650 2,366
R&D spend (4,401) (1,420) (5,821)
Admin costs (3,227) (1,976) (5,203)
Operating loss (6,912) (1,746) (8,658)
Other income/(exp.) (142) 5 (137)
Loss before tax (7,054) (1,741) (8,795)
Loss after tax (7,054) (1,741) (8,795)
Net cash 6,836 3,567 3,567
~ £5.9m raised in May 2011 ~18
Expected Milestones for 2011
Update on progress of Atu027 Jan. 2011
Update on PF-’655 in diabetic macular oedema (DME) Mar. 2011
Full year results for 2010 April 2011
Fundraising May 2011
Present interim Phase I data of Atu027 at ASCO June 2011
Completion of Phase II trial of PF-’655 in AMD (Pfizer/Quark) 2H11
Start of Phase IIb trial of PF-’655 in DME (Quark) 2H11
Extension of Dainippon Sumitomo collaboration 2H11
Start of Phase II trial of QPI-1002 in AKI (Quark/Novartis) 2H11
Further issuance of Zamore patents 2H11
Completion of Atu027 trial 2H11
19 19
Corporate plans 2011-13
Event Timing Status
Complete fundraising 1H11 Completed May 2011
Present interim Phase I results at ASCO 1H11 Completed June 2011
Complete Atu027 ‘in patient’ Phase I 2H11
Milestone on delivery of final results in collaboration 2H11 Non-dilutive funding opportunity
Announce Atu027 clinical plans 2H11
Complete restructuring 2H11
Present Phase I final results of Atu027 1H12
‘Platform technology deal’ 1H12 Non-dilutive funding opportunity
Initiate Atu027 Phase Ib 1H12
License DACC/Atu111 2H12 Non-dilutive funding opportunity
File IND for Atu134 2H12
License Atu027 2H12 Non-dilutive funding opportunity
Start Atu134 Phase I 2H12
Complete ‘in-patient’ Atu027 Phase Ib 1H13
File IND on third internal drug candidate 1H13
Announce Atu027 Phase Ib results 2H13
Complete Atu134 Phase I study 2H13
Start Atu027 Phase II trial 2H13 20
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Management
Experienced team with proven pharmaceutical development track
record
— Max Herrmann ACA, acting Chief Executive Officer and CFO
Intercytex Group PLC, Onyx Pharmaceuticals, ING
— Klaus Giese, Ph.D., Chief Scientific Officer
Chiron Corporation, UCSF and Max-Planck Institute
— Thomas Christély, Chief Operating Officer,
OXO Chemie Inc., Löschen & Partner, Enskilda Securities
— Jörg Kaufmann, Ph.D., VP Research
Chiron, Howard Hughes Medical Institute
2222
Summary
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• World leader in the discovery, development and delivery of novel RNA interference
(RNAi) therapeutics for the treatment of serious diseases
• One of the sector’s most comprehensive platforms for the discovery, development and
delivery of targeted RNAi Therapeutics
• One of the industry’s broadest RNAi clinical pipelines addressing diverse therapeutic
areas
• Validating partnerships with leading global pharmaceutical companies
• Broad intellectual property portfolio
• Strong upcoming newsflow
• Well funded following successful £5.9m fundraising in May 2011
APPENDIX
0.0
0.4
0.8
1.2
vehicle 0.03 0.1 0.3 1.0 3.0
control mg/kg ATU027/23H
hP
KN
3/h
PP
IB m
RN
A
v000m
animal # 1 2 3 4 5 6 7 8
sucrose 0.3 1.0 3.0mg/kg
PKN3
p110
Actin
Protein knock down in lung tissue (Western blot)
mRNA knock down in lung tissue (B-DNA)
Plasma level of siRNA strand (1st infusion)
0
1
10
100
1000
0 4 8 12 16 20 24
time [h]
an
tise
nse
str
an
d [p
mo
l/m
l
pla
sm
a]
0
10
1000
an
tise
nse
str
an
d [n
g/m
l
pla
sm
a]
1.0mg/kg
0.3mg/kg
0.1mg/kg
0.03mg/kg
3.0mg/kg
Sucrose 0.3mg/kg
166 bp PKN3 RNAi 5´-RACE
229 bp 16S rRNA 5´-RACE
(internal control)
cleavage site
verified
RNAi in lung tissue (5‘-RACE)
Atu027: Gene knock-down of PKN3
confirmed in preclinical studies
24
25
Atu027: Phase I Study Design
25
• Atu027 - targeting PKN3 for the treatment of advanced solid cancer
• PKN3 is a key regulator during angiogenesis and lymphangiogeneis
• Prospective, open label, single-centre, dose finding study
• Male and female subjects with advanced or metastatic solid tumors not amenable to curative standard therapy
• Approx 33 subjects - 3-6 subjects per dose level
• 11 dose levels, dose escalation: modified Fibonacci Scheme
• Treatment: 4h i.v. infusion
• 24 patients treated (end March 2011)
0
40
80
120
0 4 8 12 16 20 24
Cynomolgus Monkey Human
0
40
80
120
0 4 8 12 16 20 24
A s
trand c
oncentr
ati
on in p
lasm
a
-m
ean o
f dose
gro
ups
[ng/m
L]
Time [hours]
0.3 mg/kg
0.1 mg/kg
0.03 mg/kg
4 h infusion 4 h infusion
A s
trand c
oncentr
ati
on in p
lasm
a
-m
ean o
f dose
gro
ups
[ng/m
L]
Time [hours]
0.180 mg/kg
0.120 mg/kg
0.072 mg/kg
0.036 mg/kg
0.018 mg/kg
0.009 mg/kg
0.003 mg/kg
0.001 mg/kg
**
* Final/verfied data pending
We have achieved Predictable
Pharmacokinetics For Atu027
Predictable PK tells that Atu027 is behaving in humans as
it did in pre-clinical models
In vitro: IC50 ≈ 1 to 10 nM
27
Dose levelAtu027 - Dose (mg/kg)
(based on the siRNA content)
1 (starting dose) 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
Atu027: Positive Phase I Data to Date
27
• Phase I trial on-going – expected to complete 2H2011
− No dose limiting toxicities to date, dose escalation continuing
• Generally well tolerated to date− 173+ doses administered to 24 patients across 8 dose levels
− Up to 26 doses administered to a single patient (study
followed by compassionate use)
− No cytokine activation observed
• No pre-medication required
• > 210 timepoints analysed for complement system and cytokine activation
• Limited Atu027-related transient activation of the alternative pathway of the complement system - (as published and expected for liposomal formulations) not dose dependant
• Human plasma PK shows dose dependent increase with no evidence of drug accumulation during repeated treatment
28
Atu134 (CD31/PECAM-1): A well
validated target
200
400
600
800
24 26 28 30 32 34
Tum
or
volu
me [
mm
3]
Days post cell challenge
Silence Therapeutics
200
1200
2200
3200
12 14 16 18
Tum
or
volu
me [
mm
3]
Days post cell challenge
sucrose
siRNAPTEN-
lipoplex
Atu134
3Y1-RasV12 s.c.
Atu134
PC-3 s.c. DU-145 s.c.
0
400
800
1200
1600
25 31 37 43 49
Tum
or
volu
me
[mm
³]
Days post cell challenge
sucrose
Atu134
Atu134 shows anti-tumor activity in different established
subcutanuous tumor xenografts in comparison to control treatment.
sucrosesiRNALuc-
lipoplex
29
Efficacy of Atu134 in Various
Ectopic Tumor Xenograft Models
Thank you