Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — OPT Congress 2018
32 slides from Silence Therapeutics's conference presentation, Mar 28, 2018
Slide 1: Case Study: Identification and Development of SLN124
OPT Congress, 28 March 2018 Case Study: Identification and Development of SLN124, a Conjugated GalNAc-siRNA Therapeutic for the Treatment of Iron Overload Disorders Torsten Hoffmann, PhD, Chief Operating Officer
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 Silence
About Silence © Silence Therapeutics 2018 3
Slide 4: About Silence Therapeutics
About Silence Therapeutics Only quoted European RNA interference Our facilities player Key Performance Indicators: HQ in > Net cash position of £43M at 2nd of Jan 2018 London > Market cap: £136.5M* > EV: ~ £104M* R&D in Headcount: Berlin > 42 FTE (27 in Berlin, R&D and 15 London, Corporate and R&D)
Slide 5: 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 6: Experienced Leadership Team
Experienced Leadership Team: Strong background in discovery and development of RNA therapies Ali Mortazavi, Torsten Hoffmann, Ph.D. David Ellam, Chief Executive Officer Chief Operating Officer Chief Financial Officer Dmitry Samarsky, Ph.D. Laura Roca-Alonso, Ph.D. Michael Mulqueen, Chief Scientific
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 Completed R&D reorganisation Technology > Reducing headcount and increasing outsource
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: siRNA mechanism of action
siRNA mechanism of action 1 RNA interference is mRNA sequence for target gene X > A Nobel prize-winning mRNA discovery > A natural pathway that can be 2 harnessed to inhibit the siRNA designed specifically siRNA expression of disease- against target gene X causing genes without mRNA altering DNA 3 A
Slide 11: 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 12: GalNAc-siRNA medicines
GalNAc-siRNA medicines Schematic structure of our therapeutic molecules: Linker Binds siRNA to delivery moiety A C G U U C G A C C G A A G U C A Chemical 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 13: 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 2018 13
Slide 14: Platform performance
Platform performance 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 Targ
Slide 15: 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 16: SLN124 for the treatment of iron overload disorders
SLN124 for the treatment of iron overload disorders © Silence Therapeutics 2018 16
Slide 17: 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 18: 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. heart, liver & endocrine org
Slide 19: β-Thalassemia facts
β-Thalassemia facts >Rare blood disorder caused by mutations in the β globin gene >Patients present with ineffective erythropoiesis and chronic haemolytic anaemia >Many β-Thalassemia intermedia and all β-Thalassemia major patients require transfusions to correct anaemia >Ineffective erythropoiesis &
Slide 20: Market opportunity for iron overload disorders
Market opportunity for iron overload disorders β-Thalassemia intermedia & T. major (TDT) >Combination with transfusions & chelators to reduce frequency & dose 40,000 20,000 >Improve erythropoiesis and reduce secondary iron TDT NTDT overload burden β-Thalassemia intermedia (NTDT) >150,000 >Monotherap
Slide 21: 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 signaling pathway TMPRSS6 P > Inhibition of TMPRSS6 in hepatocytes Fe P SMAD Iron recycling induces Hepcidin expression Hepcidi > Hepcidin reduces abso
Slide 22: 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 23: SLN124 lowers iron levels for at least 6 weeks in mice
SLN124 lowers iron levels for at least 6 weeks after single administration in mice Study design d wk wk 3 wk 6 1 1 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 eek
Slide 24: 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 25: Therapeutic activity of SLN124 in hereditary haemochromatosis model - 1/2
Therapeutic activity of SLN124 in a disease model for hereditary haemochromatosis (HFE-/- mice) - 1/2 Collaboration with Study design d1 wk 3 Prof. Dr. Martina Muckenthaler SC, n=6-7 HFE-/- mice Heidelberg University, Germany TMPRSS6 mRNA (liver) Hepcidin (serum) Iron (serum) Iron (kidney) 2 .0 800
Slide 26: Therapeutic activity of SLN124 in hereditary haemochromatosis model - 2/2
Therapeutic activity of SLN124 in a disease model for hereditary haemochromatosis (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 %
Slide 27: SLN124 normalizes ROS species & improves RBC parameters in β-Thalassemia model
SLN124 normalizes ROS species & improves RBC parameters in β-Thalassemia disease model Collaboration with Study design 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 28: SLN124 development timelines – key milestones
SLN124 development timelines – key milestones Candidate nomination Pilot batch release Sterile manufacture GMP release 2017 2018 2019 Q2 Q3 Q4 Q1 Q2 Q3 Q4 H1 Start DRF Start GLP tox KOL meeting CTA filing EIH On track for CTA filing 15 months after candidate selection © Silence Therapeutics 2018 28
Slide 29: SLN124 - Summary
SLN124 - Summary > Highly potent, selective and long acting GalNAc-siRNA > Efficacious in lowering blood iron and well tolerated in healthy mice and non-human primates after single subcutaneous administration > Demonstrated therapeutic efficacy in clinically relevant animal disease models > Currentl
Slide 30: 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 30
Slide 31: 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 > Strengthen and broaden IP portfolio technologies > Expand RNAi horizons beyond
Slide 32: Acknowledgements
Acknowledgements Silence Drug Development Team Manuela Aleku, Christian Frauendorf & Jens-Uwe Künstler Silence Preclinical Drug Discovery Team Ute Schaeper, Steffen Schubert & Ulrich Zügel Silence Technology Innovation Team Marie W. Lindholm & Dmitry Samarsky Collaboration with Prof. Dr. Martina Muc