Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — AsiaTIDES 2018
44 slides from Silence Therapeutics's conference presentation, Mar 1, 2018
Slide 1: Use of Advanced siRNAs Targeted to Hepatocytes
AsiaTIDES, 1 March 2018 Use of Advanced siRNAs Targeted to Hepatocytes for the Development of Novel Drugs to Treat Liver-related 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 Our interference player facilities Key Performance Indicators: HQ in > Net cash position of £43M at 2nd of Jan 2018 London > Market cap: £136.5M* > EV: ~ £104M* Headcount: > 42 FTE (27 in Berlin, R&D and 15 London, R&D in Berlin Corporate and R&D)
Slide 5: Building a strong pipeline through 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 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 Innovation > Increas
Slide 8: Pipeline
Pipeline Building a proprietary portfolio, two projects advanced into preclinical development Our Programs 4Q 2018 Mid Mid 2019 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 2 can be harnessed to siRNA designed siRNA inhibit the expression specifically against target gene X of disease-causing genes without altering mRNA DNA 3 An
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 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 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 t
Slide 18: 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 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 erythropoies
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 TDT NTDT reduce secondary iron overload burden β-Thalassemia intermedia (NTDT) >150,000 > Monothe
Slide 21: SLN124 mechanism of action
SLN124 mechanism of action HJV BMPR Macrophages > TMPRSS6 (Transmembrane BMP Protease, Serine 6) is a negative regulator of the Ferroportin BMP/SMAD signaling TMPRSS6 P Fe pathway Iron recycling > Inhibition of TMPRSS6 in P SMAD hepatocytes induces Hepcidin Hepcidin expression > Hepcidin reduces Iro
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 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 eeks
Slide 24: Sustained iron reduction 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: SLN124 in hereditary haemochromatosis model - 1/2
Therapeutic activity of SLN124 in a disease model for hereditary haemochromatosis (HFE-/- mice) - 1/2 Study design Collaboration with d1 wk 3 Prof. Dr. Martina Muckenthaler SC, n=6-7 HFE-/- mice Heidelberg University, Germany TMPRSS6 mRNA (liver) Hepcidin (serum) Iron (serum) 2 .0 800 *** N o r m a
Slide 26: 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 in β-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 28: 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 KOL meeting IND/CTA filing EIH On track for CTA filing 15 months after candidate selection © Silence Therapeutics 2018
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: SLN226 for the treatment of alcohol use disorder
SLN226 for the treatment of alcohol use disorder © Silence Therapeutics 2018 30
Slide 31: SLN226 for the treatment of alcohol use disorder
SLN226 for the treatment of alcohol use disorder 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, effective & saf
Slide 32: 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 33: 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 34: 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 35: SLN226 mechanism of action
SLN226 mechanism of action > Alcohol dehydrogenase 2 (ALDH2) is the key alcohol metabolizing enzyme > 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 e.
Slide 36: ALDH2 GalNAc-siRNA 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 37: Liver expression of ALDH1 isoenzymes upon ALDH2 silencing
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 38: SLN226 reduces ALDH2 mRNA 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 39: Potential of SLN226 as compared to Disulfiram
Potential of SLN226 as compared to Disulfiram Reduced side effect potential (1) Hepatocyte-specific GalNAc formulation (reduction of cardio- & neurotoxic adverse effects) (2) ALDH2-specific targeting (Disulfiram inhibits ~20 off-target enzymes) Improved safety profile Higher therapy success rate (
Slide 40: 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 41: SLN226 - Summary
SLN226 - Summary > 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 i
Slide 42: Pipeline
Pipeline Building a proprietary portfolio, two projects advanced into preclinical development Our Programs 4Q 2018 Mid Mid 2019 2019 Mid 2019 Out-Licensed Programs © Silence Therapeutics 2018 42
Slide 43: 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 > Build a proprietary therapeutic GalNAc-siRNA molecules portfolio by applying validated > Strengthen and broaden IP portfolio siRNA technologies > Expand RNAi horizons beyond >
Slide 44: Acknowledgements
Acknowledgements Silence Preclinical Drug Discovery Team Ute Schaeper, Steffen Schubert & Ulrich Zügel Silence Technology Innovation Team Marie W. Lindholm & Dmitry Samarsky Silence Drug Development Team Manuela Aleku, Christian Frauendorf & Jens-Uwe Künstler Collaboration with Prof. Dr. Martina Muc