Silence Therapeutics PLC · NASDAQ:SLN

Silence Therapeutics — Investor Day (November 2017)

95 slides from Silence Therapeutics's investor day presentation, Nov 14, 2017

Slide 1: Welcome
Capital Markets Day, 14 November 2017 Welcome Dr Annalisa Jenkins, MBBS FRCP Chair of the Board
Slide 2: Forward looking statements
Forward looking statements The information contained in this presentation is being supplied and communicated to you on a Securities in the Company have not been, and will not be, registered under the United States confidential basis solely for your information and may not be reproduced, further dist
Slide 3: About me
About me My background Chief Executive Officer Head of Global R&D SVP, Head Global Surgeon lieutenant Medical Affairs commander Why did I join Silence Therapeutics? > Excited about the technology > An opportunity to support a great team > A passion for making a difference for patients living with se
Slide 4: “The year of RNAi” – The field
“The year of RNAi” – The field > Many years of academic and industry scientific research to date unlocking new opportunities > Effective delivery now realised in the clinic > First positive siRNA Phase 3 readout (Patisiran), validating the field > Several other late-stage clinical candidates making
Slide 5: “The year of RNAi” – Silence
“The year of RNAi” – Silence Key milestones in 2017 > Established a competitive GalNAc-siRNA platform technology and advanced our pipeline toward the clinic (first IND/CTA filing planned in Q4 2018) > Licensee Quark Pharmaceuticals reported positive Phase 2 results in Acute Kidney Injury and continu
Slide 6: Introduction and company strategy
Capital Markets Day, 14 November 2017 Introduction and company strategy Ali Mortazavi Chief Executive Officer
Slide 7: Our key assets
Our key assets > Powerful, reproducible and modular platform technology > Therapeutic pipeline > Validated foundational Intellectual Property in RNAi, which has been licensed (to Quark Pharmaceuticals) and we believe has potential for future licences > Business plan and strategy in place to maximise
Slide 8: We are R&D focused…
We are R&D focused… Finance BD R&D HR IP/ legal … with the management and support structures in place to drive execution © Silence Therapeutics 2017 8
Slide 9: GalNAc-siRNA medicines
GalNAc-siRNA medicines Schematic structure of our therapeutic molecules: Linker Binds siRNA to delivery moiety Chemical A C G U U C G A C C G A A G U C A modifications U G C A A G C U G G C U U C A G U siRNA GalNAc (N-Acetylgalactosamine) Mediates gene silencing Mediates targeted delivery to hepatoc
Slide 10: Our core capability
Our core capability 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 Target 1 Target 2 Targe
Slide 11: Advantageous properties of our medicines
Advantageous properties of our medicines > 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 Target KD induction Trend toward recovery to baseline leve
Slide 12: Intellectual property – Pioneers in siRNA chemical modification technology
Intellectual property – Pioneers in siRNA chemical modification technology We have 13 granted patents and 5 patent applications encompassing our foundational chemical modification technology in US and Europe Modified siRNA (example) > IP validation: Silence granted a licence in 2005 to Quark Pharmac
Slide 13: Pipeline strategy
Pipeline strategy Key criteria Target nomination Pipeline strategy > In-depth analysis and Hepatocyte KOL survey expression Business Development > Defined Target team Product Profile (TPP) Validated role in disease Clinical feasibility Target Selection R&D team team Commercially viable © Silence The
Slide 14: Platform strategy
Platform strategy ~7,000 accessible gene targets… We have the technology and the team to discover and develop a wide range of therapeutics Target & Indication In silico In vitro KD POM* Disease pPOC** NCD, CMC, CTA*** Phase I ... Selection selection screen in vivo models Regulatory Cost: $ $ $ $ $ W
Slide 15: Summary
Summary We have a powerful drug development platform with a tangible business strategy and the team to execute it © Silence Therapeutics 2017 15
Slide 16: Today’s agenda
Today’s agenda > Operational and platform technology overview Dr Torsten Hoffmann, Chief Operating Officer > Pipeline update: selected programmes in preclinical development Dr Ulrich Zuegel, Head of Preclinical Drug Discovery > Technology innovation Dr Dmitry Samarsky, Chief Scientific Officer > Pan
Slide 17: Operational & Technology Overview
Capital Markets Day, 14 November 2017 Operational & Technology Overview Torsten Hoffmann, PhD Chief Operating Officer
Slide 18: Outline
Outline 1 Organisational evolution 2 R&D operational setup 3 GalNAc-siRNA platform technology 4 Accelerating our timelines © Silence Therapeutics 2017 18
Slide 20: Building a strong pipeline through the creation of a highly functional R&D organisation
Building a strong pipeline through the creation of a highly functional R&D organisation Diverse Decision to focus on technologies GalNAc-siRNA platform Building a GalNAc-siRNA therapeutic portfolio (CRISPR, mRNA, siRNA with LNP) Outsourcing routine work 2015 2016 2017 2018 Technology- Drug Discovery
Slide 21: 2017 additions to our experienced team
2017 additions to our experienced team > Biopharma thought leader, 20 years of industry experience Dr Annalisa Jenkins, MBBS FCRP > President and CEO at Dimension Therapeutics since 2014 Non-Executive Chair > Head of global R&D at Merck Serono 2011-14 > Several leadership roles at BMS 1997-2011 10/2
Slide 23: Silence Therapeutics R&D facilities in Berlin
Silence Therapeutics R&D facilities in Berlin R&D in > Lean and agile organisation Berlin > 26 FTEs in R&D > 1,100 sqm laboratory & office space > State-of-the-art laboratories for siRNA synthesis, cellular & molecular pharmacology and innovation © Silence Therapeutics 2017 23
Slide 24: Evolving modular R&D capabilities
Evolving modular R&D capabilities In place Recently established To be established Non-clinical Drug CMC Develop- Regulatory Discovery ment Finance, Clinical Out- BD, HR, IP QA for CMC Develop- sourcing & legal ment Completed R&D reorganisation Technology > Reducing headcount and Innovation > Increas
Slide 25: R&D with focus on portfolio and innovation
R&D with focus on portfolio and innovation Technology Drug Discovery & Innovation Development > Improve performance of > Build proprietary our GalNAc-siRNA therapeutic portfolio by molecules applying validated siRNA > Strengthen and broaden technologies IP portfolio > Partner programmes in a > Expan
Slide 26: Outsourcing routine work and disease models
Outsourcing routine work and disease models Research Development Lead ID & Profiling Preclinical Clinical Target & Indication Start In silico In vitro KD POM* Disease NCD, CMC, pPOC** CTA*** Phase I Selection selection screen in vivo models Regulatory Lead identification In vivo POM NCD, CMC, Regula
Slide 28: How do siRNA medicines work?
How do siRNA medicines work? 1 mRNA sequence for target gene X mRNA RNA interference is > A Nobel prize-winning 2 discovery siRNA designed specifically against siRNA > A natural pathway that can target gene X be harnessed to inhibit the expression of disease- mRNA causing genes without 3 altering DN
Slide 29: Field leading IP position in modified siRNA
Field leading IP position in modified siRNA - importance of siRNA chemical modification Unmodified siRNA > Chemical modifications of siRNAs are required to > Prevent degradation > Increase stability and potency > Reduce immune stimulation > Silence has been pioneering advanced chemical Modified siRN
Slide 30: GalNAc-siRNA molecules
GalNAc-siRNA molecules Linker siRNA GalNAc gene silencing hepatocyte targeting Advantages of GalNAc-siRNA technology > GalNAc targets therapeutic siRNA molecules specifically to hepatocytes > Highly specific by targeting a single gene > Patient-friendly via infrequent subcutaneous administration > E
Slide 31: Gene silencing with GalNAc-siRNAs in hepatocytes
Gene silencing with GalNAc-siRNAs in hepatocytes extracellular intracellular Endosomal Escape Recognition & binding GalNAc-siRNA Recycling ASGPR Receptor (ASGPR) RNAi RISC AAA Target mRNA silencing > Intracellular delivery mediated through receptor endocytosis © Silence Therapeutics 2017 31
Slide 32: Competitive GalNAc-siRNA performance observed in higher species
Competitive GalNAc-siRNA performance observed in higher species Study design Day -7 0 4 7 14 ..weekly.. 91 SC, n=4 Cynomolgus monkeys Target protein (serum) > No altered pro- inflammatory cytokines > No skin reactions > No behavioural changes Well tolerated in higher species > Durable target inhibit
Slide 33: Continued expansion of our IP portfolio
Continued expansion of our IP portfolio In addition to our patent estate protecting our fundamental chemical modification technology, we strengthened our GalNAc-siRNA IP portfolio by filing the following patent applications in 2017: > Several lead sequences > 2 linker chemistries > 6 RNAi constructs
Slide 34: Current pipeline
Current pipeline >Building a proprietary portfolio, two projects advanced into preclinical development © Silence Therapeutics 2017 34
Slide 36: From target selection to clinical trial initiation
From target selection to clinical trial initiation Lead ID & Profiling Preclinical Clinical Target & Indication Start In silico In vitro KD POM Disease NCD, CMC, pPOC CTA Phase I Selection selection screen in vivo models Regulatory Ways to further accelerate our timelines > Bioinformatics: earlier &
Slide 37: Bridging in vitro to in vivo using human primary hepatocyte spheroid cultures
Bridging in vitro to in vivo using human primary hepatocyte spheroid cultures 3D vs 2D hepatocyte culture > Liver-specific physiology & gene expression patterns > Long living organoid structures > Extended functional ASGPR expression (up to 12 d vs. 4 h) > Repeated treatments possible Spheroid cultu
Slide 38: Strategic collaboration with Hesperos - Human “Organ-on-a-chip“
Strategic collaboration with Hesperos - Human “Organ-on-a-chip“ 4-organ chip > Single microfluidic system in vitro > Assessment of therapeutic index in 4-organ chip system • Functional mRNA silencing 10-organ chip for efficacy • On-target and off-target side effect profile > Extendable to 10-organ c
Slide 39: Summary and outlook
Summary and outlook > Transitioned from a technology oriented company to a focussed GalNAc-siRNA conjugation therapeutics company > Restructured R&D and outsourced all routine work to trusted partners > Consolidated a Drug Discovery unit and built a prioritised and competitive portfolio of therapeut
Slide 40: Selected programmes in Preclinical Development
Capital Markets Day, 14 November 2017 Selected programmes in Preclinical Development Ulrich Zügel, PhD Head Preclinical Drug Discovery
Slide 42: SLN124 Iron overload disorders
SLN124 for the treatment of Iron overload disorders © Silence Therapeutics 2017 42
Slide 43: SLN124 for the treatment of iron overload disorders
SLN124 for the treatment of iron overload disorders Goal: >Provide an effective & 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 &
Slide 44: Iron overload disorders
Iron overload disorders Affected organs by iron overload Diseases with iron overload > β-Thalassemia > Hereditary Haemochromatosis > Myelodysplastic Syndrome > Aplastic Anaemia > Sideroblastic Anaemia If untreated, iron accumulation ! in organs leads to severe damage, e.g. heart, liver & endocrine o
Slide 45: β-Thalassemia facts
β-Thalassemia facts > Rare blood disorder caused by mutations in the β globin gene > Depending on the mutations, patients present ineffective erythropoiesis and chronic haemolytic anaemia > Many β-Thalassemia intermedia and all β-Thalassemia major patients require transfusions to correct anaemia > D
Slide 46: Medical need in β-Thalassemia
Medical need in β-Thalassemia > If untreated, β-Thalassemia major is Transfusions Chelators lethal within the first years of life > β-Thalassemia intermedia & major patients depend on blood transfusions Limitations: & lifelong chelation therapy Daily > Toxicity > Lack of compliance Every Limitations
Slide 47: Market opportunity of SLN124 (US & Europe)
Market opportunity of SLN124 (US & Europe) NTDT - β-Thalassemia intermedia > Monotherapy to delay onset of severe symptoms > Reduce dietary iron overload & subsequent organ damage 40,000 20,000 TDT NTDT TDT - β-Thalassemia intermedia & major > Combination with transfusions & chelators to reduce freq
Slide 48: TMPRSS6 is a negative regulator of hepcidin and plays a key role in iron homeostasis
TMPRSS6 is a negative regulator of hepcidin and plays a key role in iron homeostasis Normal hepcidin levels control iron release Low hepcidin levels, as in β-Thalassemia from cellular stores & intestinal uptake result in high iron levels & overload in organs Liver Duodenal Enterocytes Liver Duodenal
Slide 49: Effective TMPRSS6 mRNA knockdown in primary hepatocytes
Effective TMPRSS6 mRNA knockdown in primary hepatocytes >Bioinformatic-based selection of siRNA sequences by proprietary algorithm and screen for functional activity >Various sequences identified which potently inhibit TMPRSS6 mRNA expression in target cells Human primary hepatocytes > Receptor medi
Slide 50: Silencing TMPRSS6 lowers serum iron levels in mice
Silencing TMPRSS6 lowers serum iron levels in mice Study design d1 d4 SC, n=4-6 mice TMPRSS6 mRNA (liver) Hepcidin mRNA (liver) Iron (serum) 4 40 N o r m a lis e d T M P R S S 6 m R N A N o r m a lis e d H e p c id in m R N A 1 .0 S e r u m ir o n [µ m o l/L ] 3 30 2 20 0 .5 1 10 0 .0 0 0 10 1 3 1 0
Slide 51: SLN124 lowers iron levels for at least 6 weeks after single administration in mice
SLN124 lowers iron levels for at least 6 weeks after single administration in mice Study design d1 wk 1 wk 3 wk 6 3 mg/kg SC, n=4 mice TMPRSS6 mRNA (liver) Iron (serum) 40 N o r m a lis e d T M P R S S 6 m R N A 1 .0 S e ru m iro n [µ m o l/L ] 30 20 0 .5 10 0 .0 0 1 1 3 6 w eeks 1 1 3 6 weeks PBS T
Slide 52: Sustained reduction of circulating iron levels in non-human primates
Sustained reduction of circulating iron levels after single administration in non-human primates Study design Day 1 8 22 29 43 57 71 SC, n=4 Cynomolgus monkeys Iron (plasma) P la s m a Ir o n [ % P r e d o s e ] 125 100 V e h ic l e 75 1 m g /k g S L N 1 2 4 50 3 m g /k g S L N 1 2 4 1 0 m g /k g S
Slide 53: Therapeutic activity of SLN124 in an iron overload model (HFE -/- mice) - 1/2
Therapeutic activity of SLN124 in an iron overload model (HFE -/- mice) - 1/2 Collaboration with Study design d1 wk 3 Prof. Dr. Martina Muckenthaler Heidelberg University, Germany SC, n=6-7 mice TMPRSS6 mRNA (liver) Hepcidin (serum) Iron (serum) 2 .0 800 N o r m a lis e d T M P R S S 6 m R N A S e r
Slide 54: Therapeutic activity of SLN124 in an iron overload model (HFE -/- mice) - 2/2
Therapeutic activity of SLN124 in an iron overload model (HFE -/- mice) - 2/2 Collaboration with Prof. Dr. Martina Muckenthaler Heidelberg University, Germany Transferrin saturation Haemoglobin Mean corpuscular volume M e a n c o r p u s c u la r v o lu m e [ µ m ] 3 19 60 % T r a n s f e r r in S a
Slide 55: SLN124 normalizes ROS species & improves RBC parameters in b-Thalassemia disease model
SLN124 normalizes ROS species & improves RBC parameters in b-Thalassemia disease model Study design Collaboration with d1 wk 2 wk 5 Prof. J. Vadolas & Dr. Grigoriadis Monash Medical Centre/Melbourne, Australia SC, n=6-8 Hbbth3/+ mice Reactive oxygen species (ROS) Reticulocyte proportion Haematocrit
Slide 56: Feedback by key opinion leaders on SLN124
Feedback by key opinion leaders on SLN124 International KOL workshop with clinical and regulatory experts in the field of iron overload disorders > High medical need to reduce iron overload and number of transfusions in patients > Not met by currently available therapies > SLN124 has the potential t
Slide 57: SLN124 development timelines – key milestones
SLN124 development timelines – key milestones Candidate Pilot batch release Sterile nomination manufacture GMP release 2017 2018 2019 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Start DRF Start GLP tox IND/CTA filing EIH KOL meeting On track for CTA filing 15 months after candidate selection © Silence Therapeutics 2017
Slide 58: Summary SLN124
Summary SLN124 > Highly potent, selective and long acting GalNAc-siRNA > Efficacious in lowering blood iron and well tolerated in healthy mice & non-human primates after single subcutaneous administration > Demonstrated therapeutic efficacy in clinically relevant animal disease models > Currently in
Slide 60: SLN226 for the treatment of alcohol use disorder
SLN226 for the treatment of alcohol use disorder Project 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, effect
Slide 61: Alcohol use disorder facts - 1/2
Alcohol use disorder facts - 1/2 Long term effects of alcohol abuse Consequences of alcohol abuse > Liver damage > Cardiovascular complications > Gastrointestinal damage > Central & peripheral neurological symptoms > Anxiety, depression, suicidal tendencies > Negative impact on social life Alcohol a
Slide 62: Alcohol use disorder facts - 2/2
Alcohol use disorder facts - 2/2 > Chronic alcohol abuse leads to alcoholic liver disease (ALD) – spectrum of conditions including hepatitis and cirrhosis which may eventually require liver transplantation > One third of all liver transplants due to ALD (~4,000 per year); 6-month abstinence rule whi
Slide 63: Market opportunity of SLN226 (US & Europe)
Market opportunity of SLN226 (US & Europe) Patients urgently requiring abstinence > 20-33% liver transplants due to alcohol abuse alone or in 40,000 combination with viral infection Requiring abstinence > Potentially a similar number of patients on the waiting list needing abstinence support 8,000,0
Slide 64: ALDH2 is the key alcohol metabolising enzyme
Aldehyde dehydrogenase 2 (ALDH2) is the key alcohol metabolising enzyme >ALDH2 is ubiquitously expressed >Liver is the key organ for ethanol detoxification by ALDH2 >ALDH2 is rate limiting enzyme in the ethanol metabolic pathway Ethanol Validated target ADH > Clinically: ALDH inhibitors Acetaldehyde
Slide 65: Robust ALDH2 mRNA knockdown in primary hepatocytes
Robust ALDH2 mRNA knockdown in primary hepatocytes > Bioinformatic-based selection of siRNA sequences by proprietary algorithm and screen for functional activity > Several sequences identified which potently inhibit ALDH2 mRNA expression in target cells Human primary hepatocytes N o r m a lis e d A
Slide 66: Efficient ALDH2 mRNA reduction in human primary hepatocyte spheroid cultures
Efficient ALDH2 mRNA reduction in human primary hepatocyte spheroid cultures 3D vs 2D hepatocyte culture > Liver-specific physiology & gene expression patterns > Long living organoid structures > Extended functional ASGPR expression (up to 12 d vs. 4 h) > Repeated treatments possible Spheroid cultur
Slide 67: ALDH2 GalNAc-siRNA treatment induces hepatic acetaldehyde accumulation in mice
ALDH2 GalNAc-siRNA treatment induces hepatic acetaldehyde accumulation in mice Study design d1 -4 h EtOH d10 SC, n=6 mice ALDH2 mRNA (liver) ALDH enzymatic activity (liver) Acetaldehyde (liver) 1 .5 1 .5 150 A c e ta ld e h y d e le v e ls in liv e r [n g /m g ] A ld e h y d d e h y d r o g e n a s
Slide 68: Liver expression of ALDH1 isoenzymes upon ALDH2 silencing in mice
Liver expression of ALDH1 isoenzymes upon ALDH2 silencing in mice Study design d1 -4 h EtOH d10 SC, n=6 mice ALDH2 mRNA (liver) ALDH1B1 mRNA (liver) ALDH1A1 mRNA (liver) 1 .5 2 .0 N o r m a lis e d A L D H 1 B 1 m R N A N o r m a lis e d A L D H 1 A 1 m R N A N o r m a lis e d A L D H 2 m R N A 1 .0
Slide 69: SLN226 reduces ALDH2 mRNA in liver for at least 6 weeks
SLN226 reduces ALDH2 mRNA in liver for at least 6 weeks after single administration in mice Study design d1 d10 d20 d30 d40 SC, n=5 mice, -4 h EtOH ALDH2 mRNA (liver) N o r m a lis e d A L D H 2 m R N A 1 .0 0 .5 0 .0 3 33 10 3 3 10 3 3 10 3 3 10 m g /k g CTRL ALDH2 CTRL ALDH2 CTRL ALDH2 CTRL ALDH2
Slide 70: Further characterisation of SLN226
Further characterisation of SLN226 Ethanol consumption mouse model > Assess effect of SLN226 in alcohol seeking behaviour in high alcohol preferring (HAP) mice > State of the art animal model which resembles patients’ free choice drinking and its physiological consequences Efficacy of SLN226 in high
Slide 71: SLN226 development timelines – key milestones
SLN226 development timelines – key milestones Pilot batch release Sterile manufacture KOL meeting GMP release 2017 2018 2019 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Candidate Start DRF Start GLP tox nomination IND/CTA filing* EIH* On track for IND/CTA filing in Q2 / 2019 *potentially with partner © Silence Therapeu
Slide 72: Summary SLN226
Summary SLN226 > Highly potent, selective and long acting GalNAc-siRNA > 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
Slide 73: Technology Innovation
Capital Markets Day, 14 November 2017 Technology Innovation Dmitry Samarsky, PhD Chief Scientific Officer
Slide 74: Technology Innovation efforts in 2017
Technology Innovation efforts in 2017 > Provide the best technology platform for our therapeutic pipeline > Secure our position as a world leader in RNA therapeutics > Strengthen and expand Silence’s intellectual property (IP) portfolio > Maintain freedom to operate (FTO) for our programmes and crea
Slide 75: Our therapeutic GalNAc-siRNA molecules
Our therapeutic GalNAc-siRNA molecules Linker siRNA GalNAc gene silencing hepatocyte targeting > Harness the power of RNAi to silence disease-causing genes in the liver, specifically in hepatocytes © Silence Therapeutics 2017 75
Slide 76: Delivery of GalNAc-siRNA molecules
Delivery of GalNAc-siRNA molecules > On its journey to the liver, GalNAc-siRNA molecules are exposed to various body fluids, which contain ubiquitous nucleases © Silence Therapeutics 2017 76
Slide 77: In biological fluids, unmodified GalNAc-siRNA molecules are quickly degraded
In biological fluids, unmodified GalNAc-siRNA molecules are quickly degraded Non-stabilised Serum exonucleases incubation 0h 4h 3d intact endonucleases misc enzymes degraded Stabilised 0h 4h 3d intact degraded end protection internal protection linker stabilisation >Incorporation of chemically modif
Slide 78: Mechanism of RNA backbone cleavage
Mechanism of RNA backbone cleavage nucleases >Most nucleolytic degradation reactions engage the 2’-OH and the neighbouring phosphate linkage of the RNA © Silence Therapeutics 2017 78
Slide 79: Examples of stabilising chemically modified nucleotides
Examples of stabilising chemically modified nucleotides Modified 2‘-OH Modified phosphate >Most are not naturally occurring and may cause non-specific effects and reduce silencing activity >Our strategy is to minimise the use of non-natural nucleotides while preserving or improving both stability an
Slide 80: Internal siRNA modifications for endonuclease protection
Internal siRNA modifications for endonuclease protection © Silence Therapeutics 2017 80
Slide 81: Minimising the use of non-natural nucleotides
Minimising the use of non-natural nucleotides endonucleases Hundreds of chemical modification patterns ≥50% non-natural In vitro activity: without GalNAc, with various modifications, patterns, sequences Internal siRNA modifications Serum stability: with or without GalNAc Primary hepatocyte activity:
Slide 82: Serum stability and activity of molecules with reduced non-natural nucleotide content
Serum stability and activity of molecules with reduced non-natural nucleotide content Serum stability A x1 B x2 x3 x4 x5 C x6 x7 x8 x9 intact 50% serum 3d at 37oC degraded Silencing activity in primary hepatocytes % non-natural 50% 34% 18% nucleotides >Molecules with dramatically reduced non-natural
Slide 83: In vivo activity of molecules with reduced non-natural nucleotide content
In vivo activity of GalNAc-siRNA molecules with reduced non-natural nucleotide content Study design d1 d15 SC, n=6 mice Silencing activity in mice (target mRNA levels in liver tissue) % non-natural 50% 34% 18% 2 .0 nucleotides N o r m a lis e d t a r g e t m R N A 1 .5 1 .0 0 .5 0 .0 PBS C TR L 1 0
Slide 84: Summary – Internal GalNAc-siRNA modifications for endonuclease protection
Summary – Internal GalNAc-siRNA modifications for endonuclease protection endonucleases Identified chemical modification patterns that > Reduce dramatically non-natural nucleotide content from ≥50% to less than 15% > Retain outstanding nuclease stability, as well as robust silencing activity in vitr
Slide 86: Challenges associated with non-natural end-protecting moieties
Challenges associated with the use of non-natural end-protecting moieties > Most siRNA end-protecting moieties are not naturally occurring in the human body, and may cause side effects > End-protecting moieties may add stereogenic (‘chiral’) centres that may increase complexity of compound manufactu
Slide 87: Performance of molecules with natural ‘achiral’ end-protecting moieties
Performance of GalNAc-siRNA molecules with natural ‘achiral’ end-protecting moieties Serum stability Silencing activity in primary hepatocytes 2x intact degraded 3-day serum (FBS) incubation >Single naturally occurring ‘achiral’ end-protecting moieties yield increased stability and robust gene silen
Slide 88: In vivo activity with natural achiral end-protecting moieties
In vivo activity of GalNAc-siRNA molecules with natural achiral end-protecting moieties Study design d1 d7 SC, n=6 mice Silencing activity in mice (target mRNA in liver) 1 .5 N o r m a lis e d t a r g e t m R N A 1 .0 0 .5 0 .0 PBS 10 3 10 3 m g / k g G a lN A c -s iR N A 2 x 'c h ir a l' n a t u r
Slide 89: Summary – End modifications for exonuclease protection
Summary – End modifications for exonuclease protection exonucleases Identified end-protecting moieties, which > Are naturally occurring and do not add stereogenic complexity (‘achiral’) > Yield increased nuclease stability > Show excellent activity in vitro and in vivo > Can be applied to any siRNA
Slide 91: Performance of GalNAc-siRNA molecules with stabilised linker
Performance of GalNAc-siRNA molecules with stabilised linker Serum stability Silencing activity in primary hepatocytes 50% FBS unstable stable control at 37°C 0h 4h 3d 0h 4h 3d 0h 4h 3d intact degraded nM GalNAc- siRNA >GalNAc-siRNA with stabilised linker produces robust silencing activity in primar
Slide 92: In vivo activity of GalNAc-siRNA molecules with stabilised linker
In vivo activity of GalNAc-siRNA molecules with stabilised linker Study design d0 d7 d14 d21 d28 2 mg/kg SC, n=4 mice Silencing activity in mice (target mRNA in liver) 1.5 Normalised target mRNA 1.0 0.5 0.0 PBS CTRL d7 d14 d21 d28 d7 d14 d21 d28 unstable stable >GalNAc-siRNA with stabilised linker y
Slide 93: Combining internal modification, end protection and linker stabilisation
Combining internal GalNAc-siRNA modification, end protection and linker stabilisation Study design d1 d9 SC, n=6 mice Silencing activity in mice (target mRNA in liver) % non-natural 50% 50% 32% 32% 13% 13% 1 .5 nucleotides Internal stabilisation N o r m a lis e d t a r g e t m R N A 1 .0 0 .5 End pr
Slide 94: Summary – GalNAc-siRNA innovation in 2017
Summary – GalNAc-siRNA innovation in 2017 > Designed highly stable and potent GalNAc-siRNA molecules > Reduced internal non-natural nucleotide content and ‘chiral’ end-protecting moieties by up to 85% > Internal and end-protecting patterns can be applied to any siRNA sequence, accelerating lead opti

Silence Therapeutics — Investor Day (November 2017) on 6ix

Silence Therapeutics — Investor Day (November 2017)

Slide 1: Welcome

Slide 2: Forward looking statements

Slide 3: About me

Slide 4: “The year of RNAi” – The field

Slide 5: “The year of RNAi” – Silence

Slide 6: Introduction and company strategy

Slide 7: Our key assets

Slide 8: We are R&D focused…

Slide 9: GalNAc-siRNA medicines

Slide 10: Our core capability

Slide 11: Advantageous properties of our medicines

Slide 12: Intellectual property – Pioneers in siRNA chemical modification technology

Slide 13: Pipeline strategy

Slide 14: Platform strategy

Slide 15: Summary

Slide 16: Today’s agenda

Slide 17: Operational & Technology Overview

Slide 18: Outline

Slide 19: Organisational evolution

Slide 20: Building a strong pipeline through the creation of a highly functional R&D organisation

Slide 21: 2017 additions to our experienced team

Slide 22: R&D operational setup

Slide 23: Silence Therapeutics R&D facilities in Berlin

Slide 24: Evolving modular R&D capabilities

Slide 25: R&D with focus on portfolio and innovation

Slide 26: Outsourcing routine work and disease models

Slide 27: GalNAc-siRNA platform technology

Slide 28: How do siRNA medicines work?

Slide 29: Field leading IP position in modified siRNA

Slide 30: GalNAc-siRNA molecules

Slide 31: Gene silencing with GalNAc-siRNAs in hepatocytes

Slide 32: Competitive GalNAc-siRNA performance observed in higher species

Slide 33: Continued expansion of our IP portfolio

Slide 34: Current pipeline

Slide 35: Accelerating our timelines

Slide 36: From target selection to clinical trial initiation

Slide 37: Bridging in vitro to in vivo using human primary hepatocyte spheroid cultures

Slide 38: Strategic collaboration with Hesperos - Human “Organ-on-a-chip“

Slide 39: Summary and outlook

Slide 40: Selected programmes in Preclinical Development

Slide 41: Programmes presented today

Slide 42: SLN124 Iron overload disorders

Slide 43: SLN124 for the treatment of iron overload disorders

Slide 44: Iron overload disorders

Slide 45: β-Thalassemia facts

Slide 46: Medical need in β-Thalassemia

Slide 47: Market opportunity of SLN124 (US & Europe)

Slide 48: TMPRSS6 is a negative regulator of hepcidin and plays a key role in iron homeostasis

Slide 49: Effective TMPRSS6 mRNA knockdown in primary hepatocytes

Slide 50: Silencing TMPRSS6 lowers serum iron levels in mice

Slide 51: SLN124 lowers iron levels for at least 6 weeks after single administration in mice

Slide 52: Sustained reduction of circulating iron levels in non-human primates

Slide 53: Therapeutic activity of SLN124 in an iron overload model (HFE -/- mice) - 1/2

Slide 54: Therapeutic activity of SLN124 in an iron overload model (HFE -/- mice) - 2/2

Slide 55: SLN124 normalizes ROS species & improves RBC parameters in b-Thalassemia disease model

Slide 56: Feedback by key opinion leaders on SLN124

Slide 57: SLN124 development timelines – key milestones

Slide 58: Summary SLN124

Slide 59: SLN226 Alcohol use disorder

Slide 60: SLN226 for the treatment of alcohol use disorder

Slide 61: Alcohol use disorder facts - 1/2

Slide 62: Alcohol use disorder facts - 2/2

Slide 63: Market opportunity of SLN226 (US & Europe)

Slide 64: ALDH2 is the key alcohol metabolising enzyme

Slide 65: Robust ALDH2 mRNA knockdown in primary hepatocytes

Slide 66: Efficient ALDH2 mRNA reduction in human primary hepatocyte spheroid cultures

Slide 67: ALDH2 GalNAc-siRNA treatment induces hepatic acetaldehyde accumulation in mice

Slide 68: Liver expression of ALDH1 isoenzymes upon ALDH2 silencing in mice

Slide 69: SLN226 reduces ALDH2 mRNA in liver for at least 6 weeks

Slide 70: Further characterisation of SLN226

Slide 71: SLN226 development timelines – key milestones

Slide 72: Summary SLN226

Slide 73: Technology Innovation

Slide 74: Technology Innovation efforts in 2017

Slide 75: Our therapeutic GalNAc-siRNA molecules

Slide 76: Delivery of GalNAc-siRNA molecules

Slide 77: In biological fluids, unmodified GalNAc-siRNA molecules are quickly degraded

Slide 78: Mechanism of RNA backbone cleavage

Slide 79: Examples of stabilising chemically modified nucleotides