full year results 2017 presentation - silence …...inhibit the expression of disease-causing genes...
TRANSCRIPT
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Full Year Results 2017 Presentation
6 MARCH, 2018
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Forward Looking StatementsThe information contained in this presentation is being supplied and communicated to you on a confidential basis solely for your information and may not be reproduced, further distributed to any other person or published, in whole or in part, for any purpose. In accordance with the prohibition on market abuse contained in Part VIII of the Financial Services and Markets Act 2000 (as amended) (the “Act”): (i) you must not pass this information to any person; and (ii) you must not base any behaviour in relation to any securities or other Qualifying Investments (as that term is defined in the Act) which would amount to market abuse on such information until after it is made generally available.
This presentation is being communicated in the United Kingdom only to (a) persons who have professional experience in matters relating to investments falling within Article 19(1) of the Financial Services and Markets Act 2000 (Financial Promotion) Order 2005 (the “Order”) or (b) high net worth companies and other bodies falling within Article 49(2) of the Order; or (c) persons to whom this presentation may otherwise lawfully be distributed (all such persons being referred to as “relevant persons”). This presentation is only directed at relevant persons, and any investment or investment activity to which this presentation relates is only available to relevant persons or will be engaged in only with relevant persons. Solicitations resulting from this presentation will only be responded to if the person concerned is a relevant person. Other persons should not act upon this presentation or any of its contents.
The distribution of this presentation in certain jurisdictions may be restricted by law, and persons into whose possession this presentation comes should inform themselves about, and observe, any such restrictions. Although reasonable care has been taken to ensure that the facts stated in this presentation are accurate and that the opinions expressed are fair and reasonable, the contents of this presentation have not been verified by Silence Therapeutics plc (the “Company”) or any other person. Accordingly no representation or warranty, express or implied, is made as to the fairness, accuracy, completeness or correctness of the information and opinions contained in this presentation and no reliance should be placed on such information or opinions. None of the Company, or any of its respective members, directors, officers or employees nor any other person accepts any liability whatsoever for any loss howsoever arising from any use of such information or opinions or otherwise arising in connection with this presentation. No part of this presentation, or the fact of its distribution, should form the basis of or be relied upon in connection with any contract or commitment or investment decision whatsoever. This presentation does not form part of any offer of securities, or constitute a solicitation of any offer to purchase or subscribe for securities or an inducement to enter into any investment activity. Recipients of this presentation are not to construe its contents, or any prior or subsequent communications from or with the Company or its representatives as investment, legal or tax advice. In addition, this presentation does not purport to be all-inclusive or to contain all of the information that may be required to make a full analysis of any transaction. Further, the information in this presentation is not complete and may be changed. Recipients of this presentation should each make their own independent evaluation of the information and of the relevance and adequacy of the information in this document and should make such other investigations as they deem necessary.
Securities in the Company have not been, and will not be, registered under the United States Securities Act of 1933, as amended (the “Securities Act”), or qualified for sale under the law of any state or other jurisdiction of the United States of America and may not be offered or sold in the United States of America except pursuant to an exemption from, or in a transaction not subject to, the registration requirements of the Securities Act. Neither the United States Securities and Exchange Commission nor any securities regulatory body of any state or other jurisdiction of the United States of America, nor any securities regulatory body of any other country or political subdivision thereof, has approved or disapproved of this presentation or the securities discussed herein or passed on the accuracy or adequacy of the contents of this presentation. Any representation to the contrary is unlawful.
Safe Harbour statement: this presentation may contain forward-looking statements that reflect the Company’s current views and expectations regarding future events. In particular certain statements with regard to management’s strategic vision, aims and objectives, the conduct of clinical trials, the filing dates for product licence applications and the anticipated launch of specified products in various markets, the Company’s ability to find partners for the development and commercialisation of its products as well as the terms for such partnerships, anticipated levels of demand for the Company’s products (including in development), the effect of competition, anticipated efficiencies, trends in results of operations, margins, the market and exchange rates, are all forward looking in nature.
Forward-looking statements involve risks and uncertainties that could cause actual results to differ materially from those expressed or implied by the forward looking statements. Although not exhaustive, the following factors could cause actual results to differ materially from those the Company expects: difficulties inherent in the discovery and development of new products and the design and implementation of pre-clinical and clinical studies, trials and investigations, delays in and results from such studies, trials and investigations that are inconsistent with previous results and the Company’s expectations, the failure to obtain and maintain required regulatory approvals, product and pricing initiatives by the Company’s competitors, inability of the Company to market existing products effectively and the failure of the Company to agree beneficial terms with potential partners for any of its products or the failure of the Company’s existing partners to perform their obligations, the ability of the Company to obtain additional financing for its operations and the market conditions affecting the availability and terms of such financing, the successful integration of completed mergers and acquisitions and achievement of expected synergies from such transactions, and the ability of the Company to identify and consummate suitable strategic and business combination transactions and the risks described in our most recent Admission Document.
By participating in this presentation and/or accepting any copies hereof you agree to be bound by the foregoing restrictions and the other terms of this disclaimer.
© Silence Therapeutics 2018 2
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Silence Therapeutics - Overview
© Silence Therapeutics 2018 3
> Developing RNA interference (RNAi) therapeutics, a highly innovative, specific, new class of medicines with life-saving potential for patients with serious and rare diseases
> Only quoted European RNAi drug development Company
> Proprietary platform technology builds on years of scientific research and in-house know-how
> Liver focussed – >7,000 genes are expressed in hepatocytes, many of which are therapeutic targets
> Validating licensing agreement with Quark Pharmaceuticals
> Lead pre-clinical development programme for iron overload disorders (IOD)
> Led by an international, sector-experienced Board and Executive Team
> 30 people in Berlin (R&D) and 15 people in London (Corporate and R&D)
> Explore options to expand our international capital market presence, including the potential for a NASDAQ listing
> Traded on the LSE:AIM – £138 million/$190 million mkt cap* with strong cash runway (£43 million as of 2 January 2018)
* 5 March 2018 price & conversion
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Preliminary Results - Highlights
© Silence Therapeutics 2018 4
Operational Highlights
> Generated extensive, multi-faceted, pre-clinical data demonstrating clear proof of biologic mechanism and concept for lead programmes• Data includes key findings in animal disease models representative of IOD, increasing confidence in Silence’s lead
candidate
> Licensee Quark announced positive results of a Phase 2 trial • Met primary endpoints in trial for the prevention of Acute Kidney Injury in patients at high risk following cardiac surgery• Exclusively partnered with Novartis which has an option for worldwide development and commercialisation in AKI
> Two lead programmes for iron overload disorders (IOD) and alcohol use disorder (AUD) on track to move into clinical development within 18 months• SLN124 planned to enter clinical development by the end of 2018
> Recruited five high calibre individuals to team• Leadership roles at both major global pharma and entrepreneurial biotechnology companies, as well as deep RNAi and
oligonucleotide expertise
> Commenced UK litigation action against Alnylam Pharmaceuticals and The Medicines Company• Both companies subsequently sought claims for revocation and declarations of non-infringement in respect of the patent in
suit. Silence counterclaimed for threatened infringement of the patent in suit in November 2017 • Likely that all issues between the parties will be heard at a trial beginning on, or around, 3 December 2018
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Preliminary Results - Highlights (continued)
© Silence Therapeutics 2018 5
Financial Highlights
> Loss after tax of £1.6 million (2016: £8.4 million)
> Cash and cash equivalents of £42.7 million (2016: £39.0 million)
> Net cash outflow from operating activities £9.6 million (2016: £10.1 million)
> Realised gain on disposals of Arrowhead shares £9.1 million (2016: £nil)
> Significantly bolstered balance sheet cash with sale of Arrowhead shares with proceeds totalling $24.3 million
Post Year-End Events
> New European patent (EP 1857547B) granted further protecting Silence’s key siRNA chemical modifications
that read widely across the RNAi industry
> Disposal of the final portion of Arrowhead shares with cumulative proceeds totalling $24.7 million and a cash
balance of £43 million as of 2 January 2018
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Pipeline - Building a Proprietary Portfolio
6© Silence Therapeutics 2018
SLN124
SLN226
Internal programmes advanced into preclinical development
Our Programmes
Out-Licensed Programmes
SLN124
SLN226
4Q2018
Mid 2019
Mid 2019
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RNAi/CRISPR Companies: Development Stage & Market Cap
© Silence Therapeutics 2018 7
Mar
ket C
ap ($
ml)
1,000
100
10,000
SLN
ARWR
ALNYLAM
-Patisiran-Fitusiran-Inclisiran-Givosiran
DRNA
CrisprEditas
Quark*/SLN
Intellia
Company Market Cap $MSilence 192
Arrowhead 562
Dicerna 658
Intellia 941
Editas 1,628
CRISPR 1,765
Alnylam 12,000
Pre-clinical Phase I Phase 2 Phase 3 Commercial
* Private
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Experienced Leadership Team: Strong Background in Discovery & Development of RNA Therapies
© Silence Therapeutics 2018 8
Dmitry Samarsky, Ph.D. Chief Scientific Officer
Ali Mortazavi, Chief Executive Officer
David Ellam, Chief Financial Officer
Torsten Hoffmann, Ph.D.Chief Operating Officer
Laura Roca-Alonso, Ph.D. Head of Corporate
Development
Michael Mulqueen, Head of BD & Licensing
Alison Gallafent, Head of Intellectual
Property
Ulrich Zugel, Ph.D.Head of Pre-Clinical Drug
Discovery
Linnea Elrington,Head of Human Resources
Since 2012
Since 2016
Since 2017
Since 2017
Since 2014
Since 2016
Since 2016
Since 2017
Since 2017
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Technology Innovation
> Improve performance of our GalNAc-siRNA molecules
> Strengthen and broaden IP portfolio
> Expand RNAi horizons beyond hepatocytes
> Apply to therapeutic portfolio upon validation
R&D with Focus on Portfolio and Innovation
© Silence Therapeutics 2018 9
Drug Discovery & Development
> Build proprietary therapeutic portfolio by applying validated siRNA technologies
> Partner programmes in a strategic manner
> Add new programmes in a risk-diversified manner
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GalNAc-siRNA Platform Technology
© Silence Therapeutics 2018 10
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How Do siRNA Medicines Work?
© Silence Therapeutics 2018
RNA interference is > A Nobel prize-winning
discovery> A natural pathway that
can be harnessed to inhibit the expression of disease-causing genes without altering DNA
11
We can specifically target any gene in the genome with our short interfering RNA (siRNA) molecules
mRNA sequence for target gene X
siRNA designed specifically against target gene X
1
2
Antisense strand binds to mRNA complementarily
3
mRNA degradation and gene silencing
4
mRNA
siRNA
mRNA
mRNA Antisense strand
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GalNAc-siRNA Medicines
Schematic structure of our therapeutic molecules:
© Silence Therapeutics 2018 12
siRNAMediates gene silencing
GalNAc (N-Acetylgalactosamine)Mediates targeted delivery to hepatocytes
Chemical modifications
LinkerBinds siRNA to delivery moiety
A C G U U C G A C C G A A G U C AU G C A A G C U G G C U U C A G U
How do we ensure that our medicines are protected and free to use?
> GalNAc as a targeting ligand per se is free to use> We have a robust position for our foundational chemical modification technology> We patent our linker chemistries> We patent our potent and highly specific siRNA constructs and lead sequences
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Platform technology: GalNAc-siRNA, able to mediate highly specific gene silencing in hepatocytes (liver) – “Specificity upon specificity”
~7,000 genes operate in the liver. We can target any of them by adapting the siRNA sequence, using the same technology
Platform Performance
© Silence Therapeutics 2018 13
We are able to reproducibly silence disease-causing genes using our platform technology
Target 1 Target 2 Target 3 Target 4
Single SC dose of 2-3 mg/kg in healthy mice; analysis after 1-2 weeks
P B S s iR N A 20 .0
0 .5
1 .0
No
rmal
ised
tar
get
mR
NA
C T R L s iR N A 10 .0
0 .5
1 .0
No
rmal
ised
tar
get
mR
NA
C T R L s iR N A 30 .0
0 .5
1 .0
No
rmal
ised
tar
get
mR
NA
C T R L s iR N A 40 .0
0 .5
1 .0
No
rmal
ised
tar
get
mR
NA
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Advantageous Properties of Medicines
© Silence Therapeutics 2018 14
> Subcutaneous administration, patient friendly> Long duration of action (variable depending on target gene)> Well tolerated> Our GalNAc-siRNA medicines are suitable for a wide range of indications
NADIR
Target KD induction
Trend towardrecovery to baseline levels
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$ $ $ $ $Cost:
...
Platform Strategy
© Silence Therapeutics 2018 15
CTA/IND enabling
Disease model (pPOC)
Healthy animals (POM)
~7,000 accessible gene targets…We have the technology and the team to discover and develop a wide range of therapeutics
* proof of mechanism in healthy mice** proof of concept in animal disease model*** clinical trial application
We intend to strategically partner our programmes at different stages to fully unlock the value of our platform – Rapid path to value creation
Technology deals
Phase 1/Phase 2
Phase INCD, CMC, Regulatory
Diseasemodels
KD in vivo
In vitroscreen
In silicoselection
Target & IndicationSelection
POM* pPOC** CTA***
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Intellectual Property - Pioneers in siRNA Chemical Modification Technology Since 2003
© Silence Therapeutics 2018 16
> Chemical modifications of siRNA are required to: 1) prevent degradation, 2) increase stability and potency, 3) reduce immune stimulation
> IP validation: License agreement with Quark Pharmaceuticals, which currently has two late-stage candidates in clinical development using our chemical modification technology
We have 13 granted patents and 5 patent applications encompassing our foundational chemical modification technology in US and Europe
> We believe third parties are infringing under our portfolio and we have:• Disclosed some of the relevant competitor products
• Served a claim with the UK High Court (defendants: Alnylam Pharmaceuticals and The Medicines Company) to determine whether Silence’s European patent protection is entitled to a 5-year extension for the products named in the claim
Modified siRNA (example)
> We remain focused on executing our core business of drug discovery, R&D
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SLN124 for the treatment of
Iron Overload Disorders
© Silence Therapeutics 2018 17
A case study of our platform
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Treatment of Ion Overload Disorders (IOD)
© Silence Therapeutics 2018 18
GOAL> Provide an effective and safe novel treatment option for patients with iron
overload conditions, such as β-Thalassemia
RATIONALE> Target a key modulator in iron regulation with a GalNAc-siRNA molecule
providing a highly specific, effective & safe option through inhibition of a disease relevant target gene expressed in hepatocytes
CURRENT STAGE> Preclinical development with plans to enter clinical development in
Q4/2018
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ErythropoiesisMacrophages
Duodenal Enterocytes
Hepcidin
IRON
Red bloodcells
LiverTMPRSS6
Normal hepcidin levels control iron releasefrom cellular stores & intestinal uptake
TMPRSS6 is a Negative Regulator of Hepcidin and Plays a Key Role in Iron Homeostasis
© Silence Therapeutics 2018 19
TMPRSS6 = Transmembrane Protease, Serine 6
Reduces iron levels
Improves erythropoiesis
1 Increases hepcidin levels
Reduces organ iron overload
2 43Silencing TMPRSS6
SLN124
ErythropoiesisMacrophages
Red bloodcells
Duodenal EnterocytesLiver
IRON
Hepcidin
TMPRSS6
ErythropoiesisMacrophages
Red bloodcells
Duodenal EnterocytesLiver
IRON
Hepcidin
Low hepcidin levels, as in β-Thalassemiaresult in high iron levels & overload in organs
TMPRSS6
ErythropoiesisMacrophages
Red bloodcells
Duodenal EnterocytesLiver
IRON
Hepcidin
TMPRSS6
ErythropoiesisMacrophages
Red bloodcells
Duodenal EnterocytesLiver
IRON
Hepcidin
Low hepcidin levels, as in β-Thalassemia result in high iron levels & overload in organs
TMPRSS6
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siRNA Screen and GalNAc Conjugate Testing in Primary Hepatocytes
© Silence Therapeutics 2018 20
0 .1 1 1 0 1 0 0 1 0 0 00 .0
0 .5
1 .0
G a lN A c T M P R S S 6 s iR N A [n M ]
No
rma
lis
ed
TM
PR
SS
6 m
RN
A
0 .0 1 0 .1 1 1 0 1 0 0 1 0 0 00 .0
0 .5
1 .0
G a lN A c T M P R S S 6 s iR N A [n M ]
No
rma
lis
ed
TM
PR
SS
6 m
RN
A
0 .0 1 0 .1 1 1 0 1 0 0 1 0 0 00 .0
0 .5
1 .0
G a lN A c T M P R S S 6 s iR N A [n M ]
No
rma
lis
ed
TM
PR
SS
6 m
RN
A
TMPRSS6 mRNA(receptor-mediated uptake)1° Hep (mouse)
1° Hep (cyno)1° Hep (human)
TMPRSS6 mRNA(in vitro screen – Selected siRNAs)
> Lead siRNA for TMPRSS6 identified (picomolar IC50 by transfection)> GalNAc-siRNA conjugate is functional in primary hepatocytes from different species (mouse,
human, cynomolgus)
h Hep3B cells
0.0
0.5
1.0
1.5
4 14 10 3 11 6 8 13 12 15 1 5 2 7 9UTLuc TMPRSS6 siRNA
Nor
mal
ised
TMPR
SS6
mR
NA
Lead
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1 0C T R L
1 3T M P R S S 6
1 00
1 0
2 0
3 0
4 0
Ser
um
iro
n [
µm
ol/L
]
m g /k gs iR N A
1 0C T R L
1 3T M P R S S 6
1 00
1
2
3
4
No
rmal
ised
Hep
cid
in m
RN
A
m g /k gs iR N A
1 0C T R L
1 3T M P R S S 6
1 00 .0
0 .5
1 .0
No
rma
lis
ed
TM
PR
SS
6 m
RN
A
m g /k gs iR N A
Silencing TMPRSS6 Lowers Serum Iron Levels in Mice
© Silence Therapeutics 2018 21
TMPRSS6 mRNA (liver) Hepcidin mRNA (liver) Iron (serum)
>Single subcutaneous administration results in specific KD of TMPRSS6>Upregulated Hepcidin causes reduction of blood iron levels>Proof of mechanism demonstrated
Study designd1 d4
SC, n=4-6 mice
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1P B S
1 3T M P R S S 6 s iR N A
60
1 0
2 0
3 0
4 0
Ser
um
iro
n [
µmo
l/L]
w e e k s1P B S
1 3T M P R S S 6 s iR N A
60 .0
0 .5
1 .0
No
rmal
ised
TM
PR
SS
6 m
RN
A
w e e k s
SLN124 Lowers Iron Levels for at Least 6 Weeks After Single Administration in Mice
© Silence Therapeutics 2018 22
TMPRSS6 mRNA (liver) Iron (serum)
Study design
>Long-lasting functional mRNA KD in liver >Reduction of serum iron levels for at least 6 weeks>Well tolerated with long duration of action in mice
wk 6d1 wk 1 wk 3
SC, n=4 mice, 3 mg/kg
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P B S3
C T R L1
T M P R S S 6 3
0 .0
0 .5
1 .0
1 .5
2 .0
No
rma
lis
ed
TM
PR
SS
6 m
RN
A
m g /k gs iR N A
P B S3
C T R L1
T M P R S S 6 3
0
1 0 0
1 8 0
2 0 0
2 2 0
2 4 0
[µg
Iro
n/g
dry
tis
su
e]
m g /k gs iR N A
P B S3
C T R L1
T M P R S S 6 3
0
1 0 0
2 0 0
3 0 0
Se
rum
Iro
n [
µg
/dL
]
m g /k gs iR N AP B S
3C T R L
1 T M P R S S 6
30
2 0 0
4 0 0
6 0 0
8 0 0
Se
rum
He
pc
idin
[n
g/m
L]
m g /k gs iR N A
Therapeutic Activity of SLN124 in Iron Overload Model (HFE -/- mice)
© Silence Therapeutics 2018 23
> Dose-dependent and robust silencing of TMPRSS6 mRNA in the liver
> Increase in serum hepcidin levels> Reversion of serum and kidney iron levels to
physiological values
TMPRSS6 mRNA (liver) Hepcidin (serum) Iron (serum)
Iron (kidney)
Study designd1 wk 3
SC, n=6-7 mice
Collaboration withProf. Dr. Martina MuckenthalerUniversity of Heidelberg, Germany
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Collaboration withProf. J. Vadolas & Dr. Grigoriadis Monash Medical Centre/Melbourne, Australia
SLN124 Normalises ROS Species & Improves RBC Parameters in β-Thalassemia Disease Model
© Silence Therapeutics 2018 24
-W T m ic e
P B S C T R LT h 3 /+ m ic e
T M P R S S 60
1 0 0
2 0 0
3 0 0
4 0 0
5 0 0
8 0 0
Med
ian
FI
s iR N A -W T m ic e
P B S C T R LT h 3 /+ m ic e
T M P R S S 60
5
1 0
1 5
2 0
2 5
Ret
icu
locy
tes
[%]
s iR N A -W T m ic e
P B S C T R LT h 3 /+ m ic e
T M P R S S 60
3 0
4 0
5 0
6 0
Hae
mat
ocr
it [
%]
s iR N A
> Normalisation of ROS to levels in healthy mice> Normalisation of reticulocyte proportion and improvement of haematocrit> SLN124 significantly improves erythropoiesis in animal model for
β-Thalassemia intermedia
Study designd1 wk 5
SC, n=6-8 Hbbth3/+ mice
wk 2
ROS = reactive oxygen species; RBC = red blood cells
Reactive oxygen species (ROS) Reticulocyte proportion Haematocrit
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Feedback by Key Opinion Leaders on SLN124
© Silence Therapeutics 2018 25
> High medical need to reduce iron overload and number of transfusions in patients
> Not met by currently available therapies> SLN124 has the potential to
> Reduce systemic iron> Prevent organ iron overload> Enhance erythropoiesis
... providing a significantly improved therapeutic option and better quality of life for patients living with iron overload conditions, such as β-Thalassemia
International KOL workshop with clinical and regulatory experts in the field of iron overload disorders
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>3,000,000Haemochromatosis
>150,000MDS
Market Opportunity of SLN124 (US & Europe)
© Silence Therapeutics 2018 26
Haemochromatosis
β-Thalassemia intermedia & T. major (TDT)> Combination with transfusions
& chelators to reduce frequency & dose
> Improve erythropoiesis and reduce secondary iron overload burden
β-Thalassemia intermedia (NTDT)> Monotherapy to delay onset of
severe symptoms > Reduce dietary iron overload &
subsequent organ damage
20,000NTDT
40,000TDT
Other iron overload disorders
TDT = transfusion dependent Thalassemia; NTDT = non-transfusion dependent Thalassemia
Myelodysplastic Syndrome (MDS)
SLN124 for β-Thalassemia with significant upside potential for otheriron overload disorders
*US & Europe
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Why we are Excited about SLN124?
© Silence Therapeutics 2018 27
2018: Gene silencing via siRNA is a proven concept
Mechanistic claim –treatment of iron overload disorders
QoL parameters will be improved such as transfusion frequency and drug burden of chelators
First In Class in iron overload
SLN124 has proven to increase hepcidin and reduce iron plasma levels, thus restoring iron homeostasis
Central role of hepcidin enables lowering of iron plasma levels, optimisingerythropoiesis
Launch would be expected by 2024/25 via an Orphan designation
The GalNAc conjugate targets hepatocytes in the liver, acting specifically at hepcidin’s predominant synthesis site
Pediatrics and adults will be treated
We are seeking commercialisationpartnerships
Science Indication Patient Market
What does the Mode of action bring?
How does the science connect to the diseases?
What is the patient benefit?
When and where do we want to market it?
SLN124 is highly specific targeting a single gene
SLN124: a treatment in the mono- or combination therapy setting as new SoC
We will work with patient organisations in 2018
A corporate strategy is required to access geographies in the middle and far east
SLN124 has the potential to become an essential component of the future SoC
beta-ThalassemiaMyelodysplastic SyndromesPotential for Haemochromatosis
Enables an early treatment option for the prevention of iron deposition in organs
High value product with peak sales of $600 million (BT) and $3 billion (MDS)
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SLN124 - Summary
© Silence Therapeutics 2018 28
> Highly potent, selective and long-acting GalNAc-siRNA molecule
> Efficacious in lowering blood iron and well tolerated in healthy mice and non-human primates
> Demonstrated therapeutic efficacy in clinically relevant disease models
> Currently in preclinical development with plans to enter clinical development in Q4 2018
SLN124 represents a highly valuable therapeutic candidate for patients with iron overload disorders, such as β-Thalassemia
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Outlook: Significant Milestones for the Next 12 months
© Silence Therapeutics 2018 29
> File clinical trial approval for iron overload by end of 2018
> Add further development expertise to the senior team as pipeline progresses
> Secure further validating collaborations utilising our GalNAc platform technology
> Add new targets to pipeline, and utilise next generation technology
> Continue defensive UK litigation action
2018 will be a year of continuity and building upon success to capturevalue by executing on pipeline development and leveraging its platform
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Appendix
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© Silence Therapeutics 2018 31
SLN226 for the treatment of
Alcohol Use Disorder
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SLN226 for the Treatment of Alcohol Use Disorder
© Silence Therapeutics 2018 32
GOAL> Provide an effective & safe novel treatment option for patients with alcohol
use disorder (AUD)
RATIONALE> Target ALDH2, a validated target for alcohol aversion therapy, with a
GalNAc-siRNA molecule providing a highly specific, effective & safe option through inhibition of the ALDH2 gene expressed in hepatocytes
CURRENT STAGE> Preclinical development with plans to enter clinical development in
Q2/2019*
*potentially with partner
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SLN226 Mechanism of Action
© Silence Therapeutics 2018 33
> Aldehyde dehydrogenase 2 (ALDH2) is the key alcohol metabolizing enzyme > Liver is the key organ for ethanol detoxification by ALDH2 > ALDH2 is rate limiting enzyme in the ethanol metabolic pathway
ADH
Acetate
Acetaldehyde
Ethanol
ALDH2 siRNA
Liver
Unpleasant physiological effects
Disrupt addictive cycle & alcohol seeking behavior
1 Acetaldehyde accumulation upon alcohol consumption
Abstinence2 43SilencingALDH2
Validated target
> Clinically: ALDH inhibitors e.g. Disulfiram
> Genetically in human subpopulations: alcohol flushing reactionALDH2
siRNA
Ethanol
ALDH2
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0 .1 1 1 0 1 0 00 .0
0 .5
1 .0
s iR N A [n M ]
No
rmal
ised
AL
DH
2 m
RN
A
Robust ALDH2 mRNA Knockdown in Primary Hepatocytes
© Silence Therapeutics 2018 34
> Bioinformatic-based selection of siRNA sequences by proprietary algorithmand screen for functional activity
> Several sequences identified which potently inhibit ALDH2 mRNA expressionin target cells
Human primary hepatocytes
>Receptor mediated uptake & is highly potent in the nM range
>Efficacy in primary hepatocytes (mouse, cynomolgus, human)
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1 0C T R L
3 A L D H 2
1 00
5 0
1 0 0
1 5 0
Ace
tald
ehyd
e le
vels
in li
ver
[ng
/mg
]
m g /k gs iR N A
1 0C T R L
3 A L D H 2
1 00 .0
0 .5
1 .0
1 .5
Ald
ehyd
deh
ydro
gen
ase
acti
vity
s iR N Am g /k g1 0
C T R L3
A L D H 2 1 0
0 .0
0 .5
1 .0
1 .5
No
rmal
ised
AL
DH
2 m
RN
A
s iR N Am g /k g
ALDH2 GalNAc-siRNA Treatment Induces Hepatic Acetaldehyde Accumulation in Mice
© Silence Therapeutics 2018 35
Study designd1 d10-4 h EtOH
> Single administration results in specific ALDH2 mRNA silencing> Silencing ALDH2 reduces the capacity of mouse liver to metabolise acetaldehyde> Proof of mechanism demonstrated
ALDH2 mRNA (liver) ALDH enzymatic activity (liver) Acetaldehyde (liver)
SC, n=6 mice
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SLN226 Reduces ALDH2 mRNA in Liver6 Weeks after Single Administration in Mice
© Silence Therapeutics 2018 36
> Robust mRNA reduction up to 6 weeks by single administration of 10 mg/kg> Well tolerated with long duration of action in mice
ALDH2 mRNA (liver)
3 3 3 30 .0
0 .5
1 .0
No
rmal
ised
AL
DH
2 m
RN
A
C T R L A L D H 23 3 1 0
1 0 d a y s
C T R L A L D H 23 3 1 0
2 0 d a y s
C T R L A L D H 23 3 1 0
3 0 d a y s
C T R L A L D H 23 3 1 0
4 0 d a y s
s iR N A
m g /k g
Study designd30d1 d10 d20
SC, n=5 mice, -4 h EtOH
d40
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Feedback by Key Opinion Leaders on SLN226
© Silence Therapeutics 2018 37
> Alcohol abuse & physiological dependence on alcohol is a global problem with tremendous impact on health, society and economics
> There is a clear unmet medical need to become abstinent> Not sufficiently met by currently available therapies
> Hepatologists may be more attracted to prescribing SLN226 as an extension to psychotherapy
> SLN226 has the potential to aid abstinence in alcohol dependentpatients on psychotherapy
... providing a significantly improved and safe therapeutic optionto improve compliance and alcohol abstinence for patients living withalcohol use disorder
International KOL workshop with clinical experts in the field of alcohol use disorder
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Potential of SLN226 Compared to Disulfiram
© Silence Therapeutics 2018 38
Reduced side effect potential(1) Hepatocyte-specific GalNAc formulation (reduction of cardio- & neurotoxic
adverse effects)(2) ALDH2-specific targeting (Disulfiram inhibits ~20 off-target enzymes) Improved safety profile
Higher therapy success rate(1) KD for weeks advantageous (Disulfiram requires daily in-take causing high
percentage of patients to drop out/cheat)(2) Effective support of alcohol dishabituation and high potential to reduce
therapy failure Better patient compliance
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16,000,000Alcohol-induced cirrhosis
and/or hepatitisAlcohol-induced hepatitis
8,000,000Alcohol-induced
cirrhosis
Alcoholic Liver Diseaserelated disordersAlcohol-induced cirrhosis
Market Opportunity of SLN226 (US & Europe)
© Silence Therapeutics 2018 39
Patients urgently requiring abstinence >20-33% liver transplants due to
alcohol abuse alone or in combination with viral infection
>Potentially a similar number of patients on the waiting list needing abstinence support
>Expansion to patients with alcohol use disorder strongly committed to abstinence
40,000Requiring
abstinence
>SLN226 has significant potential to aid abstinence in alcohol dependent patients on psychotherapy
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SLN226 - Summary
© Silence Therapeutics 2018 40
> Highly potent, selective and long acting GalNAc-siRNA molecule
> Induces acetaldehyde accumulation in mice after single subcutaneous administration
> Currently in preclinical development with plans to enter clinical development in Q2 2019*
> Studies initiated to show therapeutic efficacy in a clinically relevant disease model and in higher species
SLN226 represents a highly valuable therapeutic candidate for patients with AUD to maintain alcohol abstinence
*potentially with partner