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.com
2. 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.
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3. 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
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4. Overview
• 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
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5. Silence Product Pipeline
Products Indications Partners Target Delivery Pre- Phase I Phase II Target Tissue /
Clinical Organ
PF-4523655 Diabetic Macular Pfizer/Quark RTP801 Naked Local Delivery to the
(AtuRNAi) Edema siRNA Eye
Partnered programs
PF-4523655 Age-related Macular Pfizer/Quark RTP801 Naked Local Delivery to the
(AtuRNAi) Degen siRNA Eye
QPI-1002 Prevention of Delayed Novartis/ P53 Naked Systemic Delivery to
(AtuRNAi) Graft Function Quark siRNA the Kidney
QPI-1002 Acute Kidney Injury Novartis/ P53 Naked Systemic Delivery to
(AtuRNAi) Quark siRNA the Kidney
Atu027 GI & Lung & other Internal PKN3 AtuPLEX Systemic Delivery to
(AtuRNAi) cancers Tumor Endothelium
Atu134 Solid Tumors Internal AtuPLEX Systemic Delivery to
Internal programs
(AtuRNAi) Tumor Endothelium
Atu111 Acute Lung Injury Internal DACC Systemic Delivery to
(AtuRNAi) Lung Endothelium
Atu195 Solid Tumors Internal AtuPLEX Systemic Delivery to
(AtuRNAi) Tumor Endothelium
Almost half of all ongoing siRNA clinical trials are based
on Silence technology 5
6. Current Partnership Overview
Silence’s RNAi therapeutic platform has been
validated through multiple major partnerships
• 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)
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7. 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
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8. PF-4523655: Opthamology
• Silence licensed AtuRNAi technology
to Quark in 2004 2010 Market size (AMD) $3.1bn
• Pfizer licensed PF-’655 in 2006 from
Quark DME
24%
• 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 AMD
76%
• Phase II trial in age-related macular
degeneration (AMD) data due in 2H11
• Low single-digit effective royalty rate Potential Market size (DME) $1bn+
on end sales
Source: company reports
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9. QPI-1002: Renal disease
• Silence licensed AtuRNAi technology
to Quark in 2005 2010 Market size (transplant) $4.4bn
• Novartis signed $10m option for QPI- Neoral
1002 in 2010 19%
• Milestones to Silence of c.$82m
Prograf
– next milestone $3-11m on exercise of
option 42% Myfortic
10%
• Phase II trial in prevention of delayed
graft function (DGF) initiated
September 2010 (results due 2012)
• Phase II trial in acute kidney injury Cellcept
(AKI) expected to commence 2H11 29%
• Low single-digit effective royalty rate Potential Market size (AKI) $1bn+
on end sales
Source: company reports
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11. Atu027/Atu134: Market opportunity
• Anti-angiogenic market worth $8.2bn
2010 Market size (oncology) $53bn
• Both Atu027 and Atu134 are anti-
angiogenic drugs
Anti-
• Atu027 is only RNAi anti-angiogenic angiogenics,
drug in clinical development 8.2
• Atu027 will be used in the setting of Chemotherapy,
highly vascularised tumours; prostate, 19.3
lung, ovarian & melanoma Hormone
Therapies, 8.9
• Results of on-going phase I trial
expected at end 2011
• Interim data to be presented at ASCO, Other Other small
June 2011 antibodies, 10 molecules, 6.7
• Partner Atu027 in 2012
– upfront, milestones and royalties Source: company reports
Anti-angiogenic – works by disrupting blood supply to tumours 11
12. Atu027 deal structure
Big Pharm a alliances 2005-9
• Plan to partner in 2012
Upfront payment ($m)
35
30
25
• Partnering discussions initiated 20
15
10
• Typical deal structure 5
– Upfronts (double digit $m’s) 0
Lead Preclinical Phase I Phase II Phase III
– Milestones (significant)
– Royalties (double digit %)
Early stage deals 2005-9
• Variations 200
– Global rights 150
Payments ($m)
– Regional rights 100
– Ex-US/Eu rights
50
– Opt-in rights
0
Upfront R&D Milestones Equity
Source: RECAP Deloitte
13. Atu027: Strong preclinical efficacy data
• Atu027 ‘silences’ the production of 0 20 - 45 46 days
PKN3 Atu027
– PKN3 is a key regulator of blood and Avastin
lymph vessel formation
• Inhibition of PKN3 leads to:
Vehicle
– reduced oxygen supply to tumour
– reduced tumour growth/metastases
• Efficacy of Atu027 demonstrated in
multiple cancer animal models Atu027
VEGF-R-siRNA-lipoplex
– data published in peer reviewed Avastin
journals VEGF-R-siRNA-lipoplex
+ Avastin
Atu027 + Avastin
• 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 DU-146 prostate Xenograft (N = 8)
Twice weekly treatment
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14. Atu027: Phase I results promising
BEFORE AFTER
Baseline (pre-treatment) 1 week after 8th repeated treatment
Note: vanished metastatic lesion in the left lower lobe of the lung (circle)
• 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
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15. Atu134: Strong preclinical efficacy data
• Atu134 has demonstrated efficacy in a In preclinical studies
variety of preclinical cancer models
– Orthotopic models Atu134 significantly reduced
– Ectopic models tumour growth
• Atu134 has demonstrated strong 4000
* p=0.003
efficacy against primary tumour
* p=0.002 * p=0.014
Tumor volume [mm3]
3000
• Targets CD31 – well validated target
2000
• GMP manufacturing commencing
1000
• Preclinical toxicology testing due to 0
start early in 2012 Sucrose Luciferase CD31 control
(Atu134)
• IND filing expected in 2012 Breast (mammary fat pad)
• Plan to partner during Phase I
– target double digit royalty rate
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16. Atu111: treatment of acute lung injury
• 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 Organ distribution after delivery of siRNA with DACC
exquisitely selective delivery to lung 125
(see chart)
siRNA [%ID/g tissue]
100
75
• DACC delivery system leads to prolonged
50
knock-down
25
– potential for only one dose in ALI
0
• Aim to partner in 2012
– target high single digit royalties
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17. DBTC: Targeting the Liver
• Proprietary lipid-based formulation
targeting liver
• Significant market opportunities
– Liver cancer
– Ischemia reperfusion injury
– fibrosis
• DBTC delivers siRNAs primarily to liver
(see chart) Organ distribution after delivery of siRNA with DBTC
70
• DTBC delivery system leads to persistent
siRNA [%ID/tissue]
60
knock-down 50
– Single dose knocks down gene expression 40
for up to 1 wk 30
20
10
• DTBC well tolerated 0
– Dosed up to 8.3mg/kg
no functional delivery of siRNA to spleen
no knockdown in spleen tissue. 17
18. 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
19. 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
20. 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
21. 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
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22. Summary
• 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
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24. m
Atu027: Gene knock-down of PKN3
confirmed in preclinical studies
Plasma level of siRNA strand (1st infusion) Protein knock down in lung tissue (Western blot)
1000 1.0mg/kg sucrose 0.3 1.0 3.0mg/kg
antisense strand [pmol/ml
0.3mg/kg
animal # 1 2 3 4 5 6 7 8
antisense strand [ng/ml
1000
100
0.1mg/kg
plasma]
PKN3
plasma]
0.03mg/kg
10
3.0mg/kg 10 p110
1
Actin
0 0
0 4 8 12 16 20 24
time [h]
RNAi in lung tissue (5‘-RACE) mRNA knock down in lung tissue (B-DNA)
Sucrose 0.3mg/kg
hPKN3/hPPIB mRNA
1.2
229 bp 16S rRNA 5´-RACE
0.8
(internal control)
0.4
166 bp PKN3 RNAi 5´-RACE
0.0
vehicle 0.03 0.1 0.3 1.0 3.0
cleavage site control mg/kg ATU027/23H
verified 24
25. Atu027: Phase I Study Design
• 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)
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25
26. We have achieved Predictable
Pharmacokinetics For Atu027
Cynomolgus Monkey Human
4 h infusion 4 h infusion
120 120 0.180 mg/kg
A strand concentration in plasma
0.3 mg/kg
A strand concentration in plasma
- mean of dose groups [ng/mL]
0.120 mg/kg
- mean of dose groups [ng/mL]
0.1 mg/kg 0.072 mg/kg
0.03 mg/kg 0.036 mg/kg
80 80
0.018 mg/kg
*
* 0.009 mg/kg
0.003 mg/kg
40 40 0.001 mg/kg
0 0
0 4 8 12 16 20 24 0 4 8 12 16 20 24
Time [hours] Time [hours]
In vitro: IC50 ≈ 1 to 10 nM * Final/verfied data pending
Predictable PK tells that Atu027 is behaving in humans as
it did in pre-clinical models
27. Atu027: Positive Phase I Data to Date
• Phase I trial on-going – expected to complete
2H2011
− No dose limiting toxicities to date, dose escalation continuing
Atu027 - Dose (mg/kg)
Dose level
• Generally well tolerated to date (based on the siRNA content)
− 173+ doses administered to 24 patients across 8 dose levels 1 (starting dose) 0.001
− Up to 26 doses administered to a single patient (study
2 0.003
followed by compassionate use)
− No cytokine activation observed 3 0.009
4 0.018
• No pre-medication required
5 0.036
• > 210 timepoints analysed for complement 6 0.072
system and cytokine activation 7 0.120
8 0.180
• Limited Atu027-related transient activation of
9 0.253
the alternative pathway of the complement
system - (as published and expected for 10 0.336
liposomal formulations) not dose dependant 11 0.447
• Human plasma PK shows dose dependent
increase with no evidence of drug accumulation
during repeated treatment
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