Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — OPT Congress 2018
38 slides from Silence Therapeutics's conference presentation, Mar 27, 2018
Slide 1: Development of Novel Therapies Using Advanced GalNAc-siRNA Technology
OPT Congress, March 27, 2018 Development of Novel Therapies Using Advanced GalNAc-siRNA Technology Marie Wikström Lindholm, PhD, Head of Technology Innovation
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: Outline
Outline 1. About Silence Therapeutics 2. Case Study: SLN124 and iron overload disorders 3. Technology Innovation at Silence Therapeutics © Silence Therapeutics 2018 3
Slide 4: About Silence Therapeutics
About Silence Therapeutics © Silence Therapeutics 2018 4
Slide 5: About Silence Therapeutics
About Silence Therapeutics Only quoted European RNA interference Our facilities player Key Performance Indicators: HQ in London > Net cash position of £43M at 2nd of Jan 2018 > Market cap: £136.5M* Headcount: R&D in > 45 FTE (30 in Berlin, R&D and 15 London, Berlin Corporate and R&D) Listing: > AIM,
Slide 6: 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 Building a GalNAc-siRNA therapeutic portfolio technologies GalNAc-siRNA platform (CRISPR, mRNA, siRNA with LNP) Outsourcing routine work 2015 2016 2017 2018 Technology- Drug Discovery
Slide 7: 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 Technology Completed R&D re-organization to improve platform Innovation throughput an
Slide 8: Pipeline
Pipeline Building a proprietary portfolio, two projects advanced into preclinical development Our Programs 4Q 2018 Mid 2019 Mid 2019 Mid 2019 Out-Licensed Programs © Silence Therapeutics 2018 8
Slide 9: GalNAc conjugated siRNA technology
GalNAc conjugated siRNA technology © Silence Therapeutics 2018 9
Slide 10: GalNAc-conjugated siRNA
GalNAc-conjugated siRNA 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 transcript > Patient-friendly via infrequent subcutaneous administrat
Slide 11: Gene silencing with GalNAc-conjugated siRNA in hepatocytes
Gene silencing with GalNAc-conjugated siRNA in hepatocytes extracellular intracellular Endosomal Escape Recognition & binding GalNAc-siRNA Recycling ASGPR Receptor (ASGPR 1&2) RNAi RISC AAA Target mRNA silencing >Intracellular delivery mediated through receptor mediated endocytosis © Silence Therape
Slide 12: Case study: SLN124 for the treatment of iron overload disorders
Case study: SLN124 for the treatment of iron overload disorders © Silence Therapeutics 2018 12
Slide 13: Treatment of iron overload disorders
Treatment of iron overload disorders 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 thr
Slide 14: Iron Overload Disorders
Iron Overload Disorders Affected organs by iron overload Diseases with iron overload > β-Thalassemia > Myelodysplastic Syndrome > Hereditary Haemochromatosis > Aplastic Anaemia > Sideroblastic Anaemia If untreated, iron accumulation in organs leads to severe damage, e.g. in heart, liver & endocrine
Slide 15: SLN124 mechanism of action
SLN124 mechanism of action HJV BMP BMPR Macrophages > TMPRSS6 (Transmembrane Protease, Serine 6) is a negative regulator of the Ferroportin BMP/SMAD signalling pathway TMPRSS6 P > Inhibition of TMPRSS6 in hepatocytes Fe P SMAD Iron recycling induces Hepcidin expression Hepcidin > Hepcidin reduces ab
Slide 16: 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
Slide 17: SLN124 lowers serum iron levels for at least six weeks after single injection in mice
SLN124 lowers serum iron levels for at least six weeks after single injection in mice Study design d1 wk 1 wk 3 wk 6 SC, n=4 mice, 3 mg/kg 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 e
Slide 18: SLN124 - Summary
SLN124 - Summary > Highly potent, selective and long acting GalNAc-conjugated siRNA > Efficacious in lowering blood iron and well tolerated in healthy mice after single subcutaneous injection > Demonstrated therapeutic efficacy in clinically relevant animal disease models > Currently in preclinical
Slide 19: Technology Innovation: making a good thing better
Technology Innovation: making a good thing better © Silence Therapeutics 2018 19
Slide 20: R&D with focus on portfolio and innovation
R&D with focus on portfolio and innovation Technology Innovation Drug Discovery & Development > Improve performance of our GalNAc- > Build a proprietary therapeutic siRNA molecules portfolio by applying validated siRNA technologies > Strengthen and broaden IP portfolio > Partner programs in a strate
Slide 21: Unmodified GalNAc-conjugated siRNA is quickly degraded in biological fluids
Unmodified GalNAc-conjugated siRNA is quickly degraded in biological fluids 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 modifie
Slide 22: Most stabilising chemically modified nucleotides are not naturally occurring in humans
Most “stabilising chemically modified nucleotides” are not naturally occurring in humans Modified 2‘-OH Modified phosphate O Base O Base O Base O Base O O O O O O O O O R 2N O OH O F O OMe O O P P P O O Base S O Base O O Base O O O RNA - 2-'OH 2'-F 2'-OMe LNA O Base O Base O Base O Base O OH O OH O
Slide 23: siRNA modifications for endonuclease protection
siRNA modifications for endonuclease protection © Silence Therapeutics 2018 23
Slide 24: Minimizing the use of non-natural nucleotides
Minimizing 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 25: 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 26: In vivo activity of GalNAc-conjugated siRNA with reduced non-natural nucleotide content
In vivo activity of GalNAc-conjugated siRNA 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 27: Summary – GalNAc-conjugated siRNA modifications for endonuclease protection
Summary –GalNAc-conjugated siRNA modifications for endonuclease protection endonucleases Identified chemical modification patterns that > Reduce non-natural nucleotide content from ~50% to less than 15% > Retain outstanding nuclease stability, as well as robust silencing activity in vitro and in viv
Slide 28: End protection against exonucleases
End protection against exonucleases © Silence Therapeutics 2018 28
Slide 29: Challenges associated with the use of 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 can add undefined chiral centres that may increase complexity of compound manufacturing
Slide 30: Performance of GalNAc-conjugated siRNA with natural 'achiral' end-protecting moieties
Performance of GalNAc-conjugated siRNA with natural ‘achiral’ end-protecting moieties Serum stability Silencing activity in primary hepatocytes 2x intact degraded 3-day serum (FBS) incubation Engagement of single naturally occurring ‘achiral’ end-protecting moieties yields increased stability and ro
Slide 31: In vivo activity of GalNAc-conjugated siRNA with natural achiral end-protecting moieties
In vivo activity of GalNAc-conjugated siRNA with natural achiral end-protecting moieties Study design d1 d7 SC, n=6 mice Silencing activity in mice (target mRNA levels in liver tissue) 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
Slide 32: 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 33: Stabilization of the linker
Stabilization of the linker © Silence Therapeutics 2018 33
Slide 34: Performance of GalNAc-conjugated siRNA with stabilized linker
Performance of GalNAc-conjugated siRNA with stabilized 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-conjugated siRNA with stabilized linker produces robust silencing activit
Slide 35: In vivo activity of GalNAc-conjugated siRNA with stabilized linker
In vivo activity of GalNAc-conjugated siRNA with stabilized linker Study design d0 d7 d14 d21 d28 2 mg/kg SC, n=4 mice Silencing activity in mice (target mRNA levels in liver tissue) 1.5 Normalised target mR NA 1.0 0.5 0.0 P B S C TR L d7 d14 d2 1 d28 d7 d14 d21 d2 8 u n s ta b le sta b le GalNAc-co
Slide 36: Combining nucleobase modifications, end protection, and linker stabilization
Combining GalNAc-conjugated siRNA nucleobase modifications, end protection, and linker stabilization Study design d1 d9 SC, n=6 mice Silencing activity in mice (target mRNA levels in liver tissue) % 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
Slide 37: Summary – GalNAc-conjugated siRNA innovation
Summary – GalNAc-conjugated siRNA innovation > Designed highly stable and potent GalNAc-siRNA molecules > Reduced non-natural nucleotide content and “unpredicted chiral’ end- protecting modifications by up to 85% > Internal and end-protecting patterns can be applied to any siRNA sequence, accelerati
Slide 38: Acknowledgements
Acknowledgements Silence Technology Innovation Team: Dmitry Samarsky, Adrien Weingärtner, Judith Hauptmann, Lucas Bethge Silence Drug Development Team: Manuela Aleku, Christian Frauendorf & Jens-Uwe Künstler Silence Preclinical Drug Discovery Team: Ute Schaeper, Steffen Schubert & Ulrich Zügel © Sil