Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — FY2017 Earnings Presentation
40 slides from Silence Therapeutics's earnings presentation, Mar 6, 2018
Slide 1: Full Year Results 2017 Presentation
Full Year Results 2017 Presentation 6 MARCH, 2018
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: Silence Therapeutics - Overview
Silence Therapeutics - Overview > Developing RNA interference (RNAi) therapeutics, a highly innovative, specific, new class of medicines with life-saving potential for patients with serious and rare diseases > Only quoted European RNAi drug development Company > Proprietary platform technology build
Slide 4: Preliminary Results - Highlights
Preliminary Results - Highlights Operational Highlights > Generated extensive, multi-faceted, pre-clinical data demonstrating clear proof of biologic mechanism and concept for lead programmes • Data includes key findings in animal disease models representative of IOD, increasing confidence in Silenc
Slide 5: Preliminary Results - Highlights (continued)
Preliminary Results - Highlights (continued) Financial Highlights > Loss after tax of £1.6 million (2016: £8.4 million) > Cash and cash equivalents of £42.7 million (2016: £39.0 million) > Net cash outflow from operating activities £9.6 million (2016: £10.1 million) > Realised gain on disposals of A
Slide 6: Pipeline - Building a Proprietary Portfolio
Pipeline - Building a Proprietary Portfolio Internal programmes advanced into preclinical development Our Programmes SLN124 4Q2018 SLN124 Mid 2019 Mid 2019 SLN226 Out-Licensed Programmes SLN226 © Silence Therapeutics 2018 6
Slide 7: RNAi/CRISPR Companies: Development Stage & Market Cap
RNAi/CRISPR Companies: Development Stage & Market Cap ALNYLAM Company Market Cap $M -Patisiran -Fitusiran Silence 192 -Inclisiran Arrowhead 562 -Givosiran Dicerna 658 10,000 Intellia 941 Market Cap ($ml) Editas 1,628 Editas Crispr CRISPR 1,765 Alnylam 12,000 1,000 Intellia DRNA ARWR Quark* SLN /SLN
Slide 8: Experienced Leadership Team: Strong Background in Discovery & Development of RNA Therapies
Experienced Leadership Team: Strong Background in Discovery & Development of RNA Therapies Ali Mortazavi, Torsten Hoffmann, Ph.D. David Ellam, Chief Executive Officer Chief Operating Officer Chief Financial Officer Since 2012 Since 2017 Since 2016 Dmitry Samarsky, Ph.D. Laura Roca-Alonso, Ph.D. Mich
Slide 9: 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 10: GalNAc-siRNA Platform Technology
GalNAc-siRNA Platform Technology © Silence Therapeutics 2018 10
Slide 11: How Do siRNA Medicines Work?
How Do siRNA Medicines Work? 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 inhibit the expression specifically against siRNA target gene X of disease-causing genes without altering mRNA DNA 3
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: 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 14: Advantageous Properties of Medicines
Advantageous Properties of 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 levels N
Slide 15: 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: $ $ $ $ $ We
Slide 16: Intellectual Property - Pioneers in siRNA Chemical Modification Technology Since 2003
Intellectual Property - Pioneers in siRNA Chemical Modification Technology Since 2003 We have 13 granted patents and 5 patent applications encompassing our foundational chemical modification technology in US and Europe Modified siRNA (example) > Chemical modifications of siRNA are required to: 1) pr
Slide 17: SLN124 for the treatment of Iron Overload Disorders
SLN124 for the treatment of Iron Overload Disorders A case study of our platform © Silence Therapeutics 2018 17
Slide 18: Treatment of Iron Overload Disorders (IOD)
Treatment of Ion Overload Disorders (IOD) 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 opt
Slide 19: TMPRSS6 is a Negative Regulator of Hepcidin
TMPRSS6 is a Negative Regulator of Hepcidin and Plays a Key Role in Iron Homeostasis Normal hepcidin levels control iron release hepcidinlevels, Low hepcidin levels, asβ-Thalassemia as in in β-Thalassemia from cellular stores & intestinal uptake result in high iron levels & overload in organs Liver
Slide 20: siRNA Screen and GalNAc Conjugate Testing in Primary Hepatocytes
siRNA Screen and GalNAc Conjugate Testing in Primary Hepatocytes TMPRSS6 mRNA TMPRSS6 mRNA N o r m a lis e d T M P R S S 6 m R N A 1° Hep (mouse) (in vitro screen – Selected siRNAs) 1 .0 (receptor-mediated uptake) 0 .5 1.5 h Hep3B cells Normalised TMPRSS6 mRNA 0 .0 0 .0 1 0 .1 1 10 100 1000 G a lN A
Slide 21: 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 22: 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 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 1 1 3 6 weeks PBS
Slide 23: Therapeutic Activity of SLN124 in Iron Overload Model (HFE -/- mice)
Therapeutic Activity of SLN124 in Iron Overload Model (HFE -/- mice) Collaboration with Study design d1 wk 3 Prof. Dr. Martina Muckenthaler University of Heidelberg, 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 u m H
Slide 24: SLN124 Normalises ROS Species & Improves RBC Parameters in β-Thalassemia Disease Model
SLN124 Normalises ROS Species & Improves RBC Parameters in β-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 25: 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 26: Market Opportunity of SLN124 (US & Europe)
Market Opportunity of SLN124 (US & Europe) 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 > Monotherapy
Slide 27: Why we are Excited about SLN124?
Why we are Excited about SLN124? Science Indication Patient Market What does the Mode of How does the science What is the patient When and where do we action bring? connect to the diseases? benefit? want to market it? 2018: Gene silencing via siRNA is a beta-Thalassemia SLN124 has the potential to b
Slide 28: SLN124 - Summary
SLN124 - Summary > Highly potent, selective and long-acting GalNAc-siRNA molecule > Efficacious in lowering blood iron and well tolerated in healthy mice and non-human primates > Demonstrated therapeutic efficacy in clinically relevant disease models > Currently in preclinical development with plans
Slide 29: Outlook: Significant Milestones for the Next 12 months
Outlook: Significant Milestones for the Next 12 months 2018 will be a year of continuity and building upon success to capture value by executing on pipeline development and leveraging its platform > File clinical trial approval for iron overload by end of 2018 > Add further development expertise to
Slide 30: Appendix
+] SILENCE THERAPEUTICS Appendix
Slide 31: SLN226 for the treatment of Alcohol Use Disorder
SLN226 for the treatment of Alcohol Use Disorder © Silence Therapeutics 2018 31
Slide 32: 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 33: SLN226 Mechanism of Action
SLN226 Mechanism of Action > Aldehyde 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 34: 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 35: 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 36: SLN226 Reduces ALDH2 mRNA in Liver 6 Weeks after Single Administration
SLN226 Reduces ALDH2 mRNA in Liver 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 s iR N A 10 d
Slide 37: Feedback by Key Opinion Leaders on SLN226
Feedback by Key Opinion Leaders on SLN226 International KOL workshop with clinical experts in the field of alcohol use disorder > Alcohol abuse & physiological dependence on alcohol is a global problem with tremendous impact on health, society and economics > There is a clear unmet medical need to b
Slide 38: Potential of SLN226 Compared to Disulfiram
Potential of SLN226 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 (1)
Slide 39: 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 > Expan
Slide 40: SLN226 - Summary
SLN226 - Summary > Highly potent, selective and long acting GalNAc-siRNA molecule > 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 e