Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — The Oligo Meeting 2018 - OTS Seattle 2018
16 slides from Silence Therapeutics's conference presentation, Aug 1, 2018
Slide 1: Pipeline and platform progress for hepatocyte-targeted siRNAs
OTS Seattle 2018 Pipeline and platform progress for hepatocyte-targeted siRNAs Adrien Weingärtner, PhD Principal Scientist – Group Leader Drug Delivery Marie Wikström Lindholm, PhD, Head of Technology Innovation
Slide 2: Disclaimer (US)
Disclaimer (US) The information contained in this presentation is being supplied and communicated to you on a confidential basis Safe Harbour statement: this presentation may contain forward-looking statements that reflect the Company’s solely for your information and may not be reproduced, further
Slide 3: Our pipeline
Our pipeline Out-Licensed Technology to Quark Pharmaceuticals 3 Silence Therapeutics 2018 ©
Slide 4: SLN124 for the treatment of iron overload disorders
SLN124 for the treatment of iron overload disorders © Silence Therapeutics 2018 4
Slide 5: 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 and Myelodysplastic syndrome RATIONALE >Target TMPRSS6, a key modulator in iron regulation with a GalNAc-siRNA molecule providing a highly
Slide 6: Therapeutic activity of SLN124 in a disease model for hereditary haemochromatosis (HFE-/- mice)
Therapeutic activity of SLN124 in a disease model for hereditary haemochromatosis (HFE-/- mice) Collaboration with Study design d0 d 21 Prof. Dr. Martina Muckenthaler Heidelberg University, Germany SC, n=6-7 HFE-/- mice/group TMPRSS6 mRNA (liver) Hepcidin (serum) Iron (serum) Iron (kidney) 2 .0 800
Slide 7: Making a good thing better: when less is more
Making a good thing better: when less is more © Silence Therapeutics 2018 7
Slide 8: 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, Internal siRNA patterns, sequences modifications Serum stability: with or without GalNAc Screening example Primary he
Slide 9: GalNAc-conjugated siRNA with reduced 2'F modified nucleobase content
GalNAc-conjugated siRNA with reduced 2’F modified nucleobase content Serum stability Silencing activity in mice 50% serum 3 d at 37oC Study design d0 d7 SC, n=6/group intact 1 .5 degraded N o r m a lis e d t a r g e t m R N A Silencing activity in mouse primary hepatocytes 1 .0 50% 32% 13% % non- na
Slide 10: Optimizing number and position of GalNAc units
Optimizing number and position of GalNAc units © Silence Therapeutics 2018 10
Slide 11: Stepwise path to new design
Stepwise path to new design > Step 1: investigating optimal number and location for “serial clusters” synthesis direction HS O • 1-4 serinol-linked GalNAc units were conjugated to 3’ or 5’ sense or antisense strand 5' H O O P RNA 3' • All conjugates were screened for stability (tritosomes) and in vi
Slide 12: Serial serinol linked conjugate designs steps 1-2
Serial serinol linked conjugate designs steps 1-2 PS linkage PO linkage 2‘-OMe RNA 2‘-F RNA GalNAc antisense antisense antisense antisense antisense 3’-antisense 5’-sense 3’-sense 5’-antisense Varied spacer length © Silence Therapeutics 2018 12
Slide 13: Step 3: GalNAc conjugated siRNA with single GalNAc unit 3' and 5' sense strand location
Step 3: GalNAc conjugated siRNA with single GalNAc unit 3’ and 5’ sense strand location 5’/3’ 5’-tri-antennary 0h 4h 12h 24h 72h 0h 4h 12h 24h 72h Rat liver tritosome stability at 37°C and pH=5 Mouse hepatocytes incubated for 24h Grey bar: non-targeting control, white bar: untransfected cells. > Sin
Slide 14: Two single GalNAc units with 3' and 5' sense strand location increase in vivo activity
Two single GalNAc units with 3’ and 5’ sense strand location increase in vivo activity Study Design d0 d7 d14 d28 d42 d56 d70 d84 ELISA of serum protein > The new conjugate design is 2-3 times S e ru m T T R [% o f s a lin e c o n tro l] 140 more active in vivo compared to a tri- 120 antennary GalNA
Slide 15: Summary – GalNAc-conjugated siRNA design
Summary – GalNAc-conjugated siRNA design > Reduced non-natural nucleotide content to minimum 15% with retained or increased activity > Surprisingly, two single GalNAc units with 3’ and 5’ sense strand location resulted in increased stability and in vivo activity > Ongoing work includes evaluation of
Slide 16: Acknowledgements
Acknowledgements Silence Preclinical Drug Discovery and Drug Development Teams: Ute Schaeper, Steffen Schubert, Manuela Aleku, Christian Frauendorf & Jens-Uwe Künstler Silence Technology Innovation Team: Adrien Weingärtner, Judith Hauptmann, Lucas Bethge © Silence Therapeutics 2018 16
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