January 2019
Corporate Presentation
Non-Confidential Presentation
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© Silence Therapeutics 2019 2
Silence Therapeutics’ Summary
© Silence Therapeutics 2019
Notes: 1 MDS = Myelodysplastic syndrome2 As of 30 June 2018and £=$1.3
3
HQ in London
R&D in Berlin
Approx. 50 employees across both sites
• $44m of cash2 extends runway to key clinical milestones. Strong Financial Position
• Reproducible, proprietary gene silencing (RNAi) therapeutics platform, rapidly generating internal pipeline and diversifying out-licensing options
Valuable Platform
• SLN124 (beta-thalassemia & MDS1) planning to enter the clinic in H2 2019 after promising efficacy signals in animal modelsHaematology
• Focused on targeting indications in rare diseases & large population targets, including new medicine for cardiovascular disease (SLN360)
Target Selection
• Over 15 years of tenured oligonucleotide R&D expertise; growing clinical team, and experienced biopharma management team
Strong Experienced
Team
Silence: Operational Highlights
• New leadership in place with the recruitment of Dr David Horn Solomon as Chief Executive Officer, an experienced public company biotech CEO, board member and biotech investor.
• The field is advancing: Gene-silencing as a therapeutic modality was granted its first drug approval by the U.S. Food and Drug Administration (FDA) on August 10 2018 for Onpattro™, validating RNAi as a class of drugs that now have a clear path to market.
• Positive regulatory feedback and promising data in clinically relevant animal disease models representative of iron overload disorders, increases confidence in Silence’s lead candidate SLN124, with initiation of Phase 1b study anticipated in H2 2019.
• New RNAi medicine advanced – SLN360 for the treatment of LP(a) associated cardiovascular disease. Positive preclinical data generated in NHP. CTA/IND planned for H2 2020.
• Out-licenced technology, QPI-1002 for potential prevention of acute kidney injury progressed to Phase 3 dosing by Quark Pharmaceuticals, Inc.
© Silence Therapeutics 2019 4
Experienced Leadership Team
© Silence Therapeutics 2019
Richard Jenkins VP Clinical Development
David Horn SolomonCEO & President CEO
Rob Quinn, Interim CFO
Laura Roca-Alonso, Ph.D. VP Corporate Development
Linnea Elrington,VP Human Resources
Since 2018 Since 2017
Marie Wikstrom LindholmVP Technology Innovation
Deep Background in Discovery & Development of RNA Therapies With Strong Biopharma Experience
5
Since 2018 Since 2018
Since 2014 Since 2017
Michael Mulqueen, VP BD & Licensing
Since 2017
Our Pipeline
© Silence Therapeutics 2018
© Silence Therapeutics 2019 6
Out-Licensed Technology to Quark Pharmaceuticals
Iron Overload Disorders:SLN124 for β-Thalassemia and Myelodysplastic Syndrome
• SLN124 is an GalNAc-siRNA targeting TMPRSS6 in hepatocytes. Inhibition of TMPRSS6 induces Hepcidin expression, thereby reducing circulating iron levels
• Initially targeting β-Thal and MDS. Expansion opportunities include Hereditary Hemochromatosis
© Silence Therapeutics 2019 7
Overview Value and Drivers Current Status and Next Steps
• Peak US/EU sales of $1.4bn (MDS) and $300m (β-Thal) – at 20% market share
• CTA planned in Q2 2019, with first patient dosed in Phase 1b study in Q3 2019
• First interim results expected in mid 2020
• Phase 1b planned to run over 2019-2021 (c. $20m)
• Planning to progress straight into pivotal trials in 2022 (c. $50m) with launch expected in 2026
SLN360, Silencing LP(a) to treat CVD
• Lipoprotein (a) (“LP(a)”) is a significant risk factor for premature coronary heart disease & unstable angina and is associated with increased risk of myocardial infarction (MI).
• SLN360 demonstrates strong LP(a) reduction in serum and is now ready to enter IND-enabling studies.
• Phase 1 studies to commence in 2020.
Opportunity
• Entry Indication: people with familial LP(a) elevation at high risk of cardiovascular disease (CVD) {~600,000 in US and Europe}
• Expansion Potential: subjects treated with statins (+/- anti-PCSK9) who are still at risk of CV events associated with elevated LP(a) {>20M in US and Europe}
© Silence Therapeutics 2019 8
GalNAc-siRNA Platform Technology
© Silence Therapeutics 2019 9
Modifying Molecular Design to Enhance Performance
© Silence Therapeutics 2019 10
siRNA modification pattern
GalNAc compositionEnd stabilization
Linker composition
• Modification pattern: reduced number of non-natural modifications• End stabilization: increased circulation half-life, activity and duration of action• Linker: simplified synthesis, increased activity • GalNAc: lower dosing via optimization of number & placement of monomers
Evolving a better molecule: Increasing activity & duration, lowering COGS and dosing
• Gen 1 Gen 2 Gen 3 Gen 4
Evolution of Our GalNAc-siRNA Platform
© Silence Therapeutics 2019 11
2016 2017 2018
GEN2
GEN1 GEN3
GEN4
• Patents filed• Entered pipeline in Q2 2018• Advantages: Improved safety profile and
COGS, and FTO further strengthened
• Served to transition to conjugate technology, establishing baseline performance. No FTO
• Patents filed• Clinical stage in 2019 (SLN124) and used in
late pre-clinical stage programmes (SLN226, CVD)
• Robust performance, competitive to peers
• Patents filed• Further optimisation ongoing• Plans to enter the pipeline in early 2019• Advantages: improved potency, COG and
safety
Different GalNAc unit numbers and positioning
Reduced non-naturalmodifications
Reproducibly silencing disease-associated genes using our proprietary platform technology
© Silence Therapeutics 2019 12
Platform technology with freedom to operate: GalNAc-siRNA, able to mediate highly specific gene silencing in hepatocytes (liver) – “Specificity upon specificity”
Patient friendly: Subcutaneous delivery and infrequent dosing (monthly or longer). Well tolerated.
~7,000 genes operate in the liver. Silence can target any of them by adapting the siRNA sequence, using the same technology.
Target 1 Target 2
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
SLN124 for the treatment of
Iron Overload Disorders
© Silence Therapeutics 2019 13
Treatment of Iron Overload Disorders (IOD)
14
GOAL• Provide an effective and safe novel treatment option for
patients with iron overload conditions with infrequent s.c. dosing
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 (TMPRSS6) expressed in hepatocytes
CURRENT STAGE• Preclinical development with plans to enter clinical
development in H2 2019 after Q2 2019 CTA filing
Affected organs
Iron overload disorders:• Myelodysplastic Syndrome
(MDS)• β-Thalassemia• Hereditary
Haemochromatosis• HSC transplant• Aplastic Anaemia• Sideroblastic AnaemiaIf untreated, iron accumulation in organs leads to severe organ damage,
© Silence Therapeutics 2019
Market Opportunity of SLN124
© Silence Therapeutics 2019 15
~40,000 TDT1
~20,000 NTDT2
US and EU patients
>100,000
β-Thalassemia
MDS3
SLN124 aims to:1. Reduce organ iron levels &2. Enhance erythropoiesis
Reduced transfusion frequency & Secondary iron overload burden
Standard of Care
Benefits of SLN124 Advantages v CompetitionSoC:
Transfusions + Chelators
Luspatercept
Gene therapy
Hepcidin mimetics
Antisense RNA
Quality of Life
Safety
Compliance
Organ iron levels
Less frequent dosing
Advantages Competition
Notes: 1 TDT = Transfusion Dependent Thalassemia 2 NTDT = Non Transfusion Dependent Thalassemia 3 MDS = Myelodysplastic Syndrome
SLN124 Mechanism of Action: Increasing Hepcidin by Silencing its Repressor TMPRSS6
© Silence Therapeutics 2019 16
• TMPRSS6 (Transmembrane Protease, Serine 6) is a negative regulator of the BMP/SMAD signaling pathway
• Inhibition of TMPRSS6 in hepatocytes induces Hepcidin expression
• Hepcidin reduces absorption of dietary iron and the release of iron from cellular storage, thereby reducing circulatory iron levels
• The liver is the predominant source of Hepcidin
TMPRSS6
BMPRHJV
SMADP
Hepcidin induction
BMP
P
Enterocytes
Ferroportin
Iron recycling
Hepatocytes
Fe
Iron absorption
Macrophages
Fe
HAMPDNA
Hepcidin
Ferroportin
Reduces iron levels
Improves erythropoiesis
1 Increases Hepcidin levels
Reduces anemia & iron overload
2 43Silencing TMPRSS6
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 2019 17
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
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 a Disease Model of Hereditary Haemochromatosis (HFE-/- mice)
© Silence Therapeutics 2019 18
• Dose-dependent and robust silencing of TMPRSS6 mRNA in the liver
• Increase in serum hepcidin levels• Reduction 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 HFE-/- mice
Collaboration withProf. Dr. Martina MuckenthalerHeidelberg University, Germany
Kruskal-Wallis test with uncorrected Dunn‘s test against non-targeting control CTRL
p=0.0007
p<0.0001
p=0.0042
p<0.0001
p=0.0263
p=0.0325
Collaboration withProf. J. Vadolas & Dr. Grigoriadis Monash Medical Centre/Melbourne, Australia
SLN124 Reduces ROS and Improves RBC Parameters in a β-Thalassemia Disease Model
© Silence Therapeutics 2019 19
• Reduction 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
-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
p = 0 .0 0 6 9
-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
p = 0 .0 0 4 2
-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
p = 0 .0 0 7 6
We are Planning to Initiate a Multicentre, Randomised, Placebo Controlled Phase 1b in 2019
This is a 2 part first-in-human, multicenter, randomized placebo controlled single ascending and multiple dose study to assess the preliminary safety, tolerability, PK and efficacy of SLN124 administered subcutaneously for the treatment of non-transfusion dependent thalassemia and low risk myelodysplastic syndrome.
Study design
> Part A:
• Single dose escalation study to evaluate the dose response to SLN124 with a view to identify the most appropriate dose to bring forward into the multiple dose portion of the study
• Primary aim to determine the safety and tolerability of SLN124 for the treatment of non-transfusion dependent β-thalassemia
> Part B:
• Bring forward the most efficacious and best tolerated dose to evaluate multiple administrations of SLN124 on hematinic parameters in patients with β-thalassemia and MDS
• Primary aim to determine the safety and tolerability of multiple doses of SLN124 for the treatment of non-transfusion dependent β-thalassemia and low risk myelodysplastic syndrome
20© Silence Therapeutics 2019
2019 2020 2021 2022Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2
The Phase 1b will Include β-Thalassemia and MDS Patients with Interim Results Expected in 2020
21
14w 4w Cohort 1, SD, P=2 A=6, 0.3 mg/kg
Interim analysis, potential DP
Interim analysis and preliminary analysis on multiple dose
Part A analysis and final decision on multiple dose
Cohort 5, MD, P=5 A=10, x mg/kg20w 12w
Cohort 6, MD, P=5 A=10, x mg/kg
5w
Part B flash results
β-Thalassemia
MDS
Cohort 3, SD, P=2 A=6, 3 mg/kg10w 4w
Cohort 2, SD, P=2 A=6, 1 mg/kg
Cohort 4, SD, P=2 A=6, 10 mg/kg10w 4w
Optional cohort 4a, SD, P=2 A=6, x mg/kg10w 4w
5w
Interim analysis, potential DP
10w 4w
Interim analysis, potential DP
LEGEND
xw Cohort rec = x weeks
yw Follow up = y weeks
SD = Single dose
MD = Multiple dose
P = Number of subjects receiving placeboA = Number of subjects receiving active agent
xw LPLV to DBL = y weeks
20w 12w
© Silence Therapeutics 2019
SLN124 Summary
• Preclinical package: Robust data generated in several disease models.
• Status: Non-clinical development work ongoing, with CTA filing expected in Q2 2019. Orphan Designation granted for β−Thalassaemia and application planned for MDS.
• Clinical plans: Phase 1b planned in patients (β−Thalassaemia and MDS). Network of KOL’s established.
• Dosing regimen: Patient-friendly, with monthly or less frequent dosing expected and subcutaneous administration route.
• Regulatory: Positive feedback received at Scientific Advice meetings with both the UK (MHRA) and German (BfArM) national regulators.
• SLN124 is commercially viable compared to gene therapy, which has a heavy burden on patients versus a monthly SubQ.
© Silence Therapeutics 2019 22
SLN360 for the treatment of
LP(a)
© Silence Therapeutics 2019 23
LP(a) is an Independent Risk Factor for CVD
© Silence Therapeutics 2019 24
> LP(a) is a validated target in humans. LP(a) excess isdetected in patients with premature CVD:
> LP(a) is only minimally confounded by typical riskfactors such as smoking, blood pressure or diabetes.
> High unmet need - Apheresis is the only approachthat can reduce LP(a) levels by a large amount,however is invasive and burdensome: procedurelasts 70min-2h, can be performed up to every week
Peak aortic Jet velocity (m/s)
Patients with lowLp(a) levels
Patients with highLp(a) levels
Peak aortic Jet velocity (m/s)
Up to 2-fold higher
hemodynamic progression rate
on echo and need for AVR
Peak aortic Jet velocity (m/s)
Tsimikas 2017
Adjustment for additional risk factors does not produce dramatic changes
• High LP(a) associates with CHD, unstable angina,myocardial infarction (MI) and progression of aortic valvecalcification and coronary artery vasopasm (CAVS)
• High LP(a) levels have been shown to predict a 2-4 foldincrease in risk of MI and CVD
• Adding LP(a) levels ≥80th percentile to conventional riskfactors improves MI and CHD risk prediction
LP(a) has Prothrombotic, Proinflammatory and Proatherogenic Properties
© Silence Therapeutics 2019 25
Proinflammatory
ProthromboticProatherogenic
Macrophage IL-8 expression
Monocyte cytokine releaseMonocyte cytokine release
Monocyte chemotaxis/transmigration
Carries MCP-1
EC binding
Upregulation of adhesion molecules
SMC proliferation
Proteoglycan matrix binding
Foam cell formation
Necrotic core formation
Lesion calcification
Plasminogen activation
Fibrin degradation
EC PAI-1 expression
TFPI activity
Platelet responsiveness
LP(a
) act
iviti
es
Adapted from Tsimikas et al 2017
> The LP(a) complex is composed of two different proteins encoded by the LPA and the APOB genes and a lipid particle, both expressed in hepatocytes
Our approach to reducing LP(a) levels
© Silence Therapeutics 2019
Proof of mechanism achieved> Highly competitive dataset generated in non-human primates
> Over 85% KD at NADIR for single 3mg/kg injection with 50% KD still observed 2 months post-treatment
> Multiple dosing at a 3mg/kg dose level resulted in sustained reduction of Lp(a) serum levels (>90%) for at least over two months after first dose (max ~>95% KD). Similar outcome after single subcutaneous 9mg/kg injection
26
SLN360 summary
© Silence Therapeutics 2019 27
Rationale> LP(a) is a low-density lipoprotein produced predominantly by the liver and composed of
Apo(a) and Apo B, both hepatocyte expressed genes.
> Genetically defined high LP(a) serum levels are unaffected by diet and exercise and arean independent risk factor for CVD. There is no specific LP(a) targeting therapy availableat the moment.
> An LPA silencing siRNA would provide a specific, safe and durable approach forreducing LP(a) levels in high risk patients.
Our Programme> A potent lead sequence has been selected and tested in vivo in non-human primates
(NHP).
> Proof of mechanism has been achieved in NHP: dose dependent reduction in both LPA(liver mRNA) and LP(a) (serum protein) observed, with max 95% KD observed aftermultiple dosing.
> Our drug compares positively against published data by competitors, suggesting asuperior performance.
>IND/CTA is planned for H2 2020
Expected Newsflow & Company Milestones
© Silence Therapeutics 2019 28
H1 2019 H2 2019
SLN124
File CTA X
First In Human Dosing X
SLN360
Lead candidate nomination X
2018 New Targets
pPOC in mice X
Final candidate nomination X
Platform Strengthening
Gen4 toolbox validation and in use X
Quark Out-License in QPI-1002
First interpretative results for DGF Phase 3 study expected X
Thank you