Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — Annual Needham Healthcare Conference 2020
31 slides from Silence Therapeutics's conference presentation, April 2020
Slide 1: Silence Therapeutics Corporate Presentation
Silence Therapeutics Corporate Presentation April 2020 © Silence Therapeutics 2019 CONFIDENTIAL 1
Slide 2: Disclaimer
Disclaimer The information contained in this presentation is being supplied and communicated to you solely for your Safe Harbour statement: this presentation may contain forward-looking statements that reflect the Company’s information and may not be reproduced, further distributed to any other pers
Slide 3: Silence Therapeutics - Summary
Silence Therapeutics - Summary > Reproducible, proprietary gene silencing (RNAi) therapeutics platform, rapidly generating Valuable Platform internal pipeline and out-licensing options. Platform validated through collaborations with HQ in London AstraZeneca, Mallinckrodt and Takeda > SLN360 (CVD wit
Slide 4: 2019 Accomplishments & 2020 Outlook
2019 Accomplishments & 2020 Outlook 2019 2020 SLN360 Strengthened team SLN360 People Pre-IND meeting held with Management team On track for IND/CTA in H2 Recruitment of new CEO FDA in Dec. strengthened with several 2020. ongoing. IND-enabling studies new hires, including Giles Expect First Patient d
Slide 5: Leadership
Leadership Interim Executive Chairman Head R&D, CMO CFO Iain Ross Giles Campion Rob Quinn Appointed as Chairman in April 2019 Former Chief Medical Officer and SVP R&D Chartered accountancy training at Deloitte and Executive Chairman in Dec 2019 at Prosensa (2009-2016), playing a major before j
Slide 6: GalNAc (Ligand) Conjugation Allows for Delivery of siRNA to Liver Cells
GalNAc (Ligand) Conjugation Allows for Delivery of siRNA to Liver Cells Subcutaneous Hepatocyte injection Extracellular Intracellular GalNAc-siRNA Endosomal escape Liver Recognition & binding Recycling ASGPR GalNAc-siRNA AAA RNAi RISC AAA Hepatocytes Receptors (ASGPR) Target mRNA silencing Naturally
Slide 7: Reproducibly Silencing Disease-Associated Genes Using our Proprietary Platform Technology
Reproducibly Silencing Disease-Associated Genes Using our Proprietary Platform Technology Platform delivery technology: GalNAc-siRNA able to mediate highly specific gene silencing in Target 1 Target 2 hepatocytes (liver) – “Specificity upon specificity”. N o r m a lis e d ta r g e t m R N A N o r m
Slide 8: A Competitive Platform, With Continuous Fine-Tuning to Further Improve Performance
A Competitive Platform, With Continuous Fine-Tuning to Further Improve Performance SLN360 AMG 890 1 .4 3x3mg/kg weekly doses 1 .2 L p ( a ) n o r m a liz e d 1 .0 0 .8 0 .6 C o n tro l 0 .4 3 x 3 m g /k g 0 .2 0 .0 0 7 1 4 2 0 3 0 4 0 5 0 6 0 7 0 D a y siRNA modification pattern GalNAc End Linker co
Slide 9: Development Pipeline
Development Pipeline © Silence Therapeutics 2020 9
Slide 10: Collaboration with AstraZeneca for the Treatment of Cardiovascular, Renal, Metabolic and Respiratory Diseases
Collaboration with AstraZeneca for the Treatment of Cardiovascular, Renal, Metabolic and Respiratory Diseases • Research, Collaboration, Option and Licence agreement to discover and develop RNA interference therapeutics for the treatment of serious diseases. > Draws on Silence’s extensive experience
Slide 11: Our siRNA Platform is Validated Through Strategic Partnerships with Leading Pharma Companies
Our siRNA Platform is Validated Through Strategic Partnerships with Leading Pharma Companies January 2020 – Silence Therapeutics entered into a July 2019 - Silence Therapeutics entered into a Research and Technology Evaluation Agreement with Takeda to explore Collaboration Agreement with Mallinckrod
Slide 12: SLN360 for the treatment of Cardiovascular Disease with high Lp(a)
SLN360 for the treatment of Cardiovascular Disease with high Lp(a) © Silence Therapeutics 2020 12
Slide 13: Lp(a): What is it?
Lp(a): What is it? Discovered in 1963 by Kare Berg Expressed predominantly in the liver > Highly variable in size > Expression restricted to human and non-human primates Lp(a) levels are genetically defined > Not modified through lifestyle interventions Contributes to total LDL-C Considered to be pr
Slide 14: Lp(a) Distribution in the Population
Lp(a) Distribution in the Population Most biological entities show Lp(a) distribution is skewed a normal distribution in a with 20% of the population population with higher than 50 mg/dL Nordestgaard B Eur Heart J: 2010 31:2844 © Silence Therapeutics 2020 14
Slide 15: Cardiovascular event risk increases with high Lp(a)
Cardiovascular event risk increases with high Lp(a) Fold Increase in risk with high Lp(a) Risk Ratio: • The probability of one outcome versus another. Mortality • A risk ratio of 2 is double •1.2 to the risk. 1.4 • A risk of 0.5 is half the risk Ischemic Myocardial Stroke Infarction •1.2 to •2 to 3
Slide 16: Up to 700 million globally in top 10% Lp(a) levels
Up to 700 million globally in top 10% Lp(a) levels Global Prevalence of Elevated Lp(a) [millions] Prevalence 20% 10% 5% 1% Lp(a) [mg/dL] 60 90 116 180 USA 64 30 16 3.2 EU 150 75 37.5 7.5 Globally 1400 700 350 70 Varvel et al Arterioscler Thromb Vasc Biol. 2016;36:2239 Source: US laboratory Database
Slide 17: SLN360 Targets Lp(a) - an Independent Risk Factor for Cardiovascular Disease
SLN360 Targets Lp(a) - an Independent Risk Factor for Cardiovascular Disease Lp(a) levels are genetically determined Increased MI Risk with increased Lp(a) Recognized as a major untreated risk factor in cardiovascular disease Lp(a) levels are not significantly modifiable through diet or approved pha
Slide 18: Sustained and Deep Lp(a) Knockdown Demonstrated in Animal Model
Sustained and Deep LP(a) Knockdown Demonstrated in Animal Model Serial serum collection 1 5 0 L p (a ) le v e ls ± S D ) d-15 d0 d7 d14 d63 C o n tro l Serum Lp(a) reduction s e ru m 1 0 0 3 m g /k g Serum 9 m g /k g baseline siRNA N o r m a lis e d B L 3 x 3 m g /k g sc 5 0 (M e a n Group mg/kg Day
Slide 19: SLN360 Summary
SLN360 Summary Rationale > Lp(a) is a low-density lipoprotein produced predominantly by the liver and composed of Apo(a) and Apo B, both hepatocyte expressed genes. > Genetically defined high Lp(a) serum levels are unaffected by diet and exercise and are an independent risk factor for CVD. There is
Slide 20: SLN124 for the treatment of Iron Overload Disorders
SLN124 for the treatment of Iron Overload Disorders © Silence Therapeutics 2020 20
Slide 21: Market Opportunity of SLN124
Market Opportunity of SLN124 US and EU patients Standard of Care β-Thalassemia MDS3 ~40,000 TDT1 >100,000 ~20,000 NTDT2 Onset: from birth, but notable Onset: Typically >70y incidence of NTDT beyond 35 Orphan indications Benefits of SLN124 Advantages v Competition SLN124 aims to: Quality of Life SoC:
Slide 22: SLN124 Mechanism of Action: Increasing Hepcidin by Silencing its Repressor TMPRSS6
SLN124 Mechanism of Action: Increasing Hepcidin by Silencing its Repressor TMPRSS6 Macrophages HJV BMPR BMP Ferroportin >TMPRSS6 (Transmembrane Protease Serine 6) is a negative regulator of the Fe TMPRSS6 P BMP/SMAD signaling pathway P Iron recycling >Inhibition of TMPRSS6 in hepatocytes SMAD Hepcid
Slide 23: 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 1 .0 N o r m a lis e d T M P R S S 6 m R N A 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 24: SLN124 Ameliorates Splenomegaly and Improves Anemia in β-Thalassemic Mice
SLN124 Ameliorates Splenomegaly and Improves Anemia in β- Thalassemic Mice Study design Collaboration with Hbbth3/+ mice, 2-4 m, n=5-8 d1 wk 2 wk 5 2x 3mg/kg SLN124 s.c. Dr. J. Vadolas & Dr. G. Grigoriadis 1.25 mg/ml deferiprone in drinking water Monash Medical Centre/Melbourne, Australia Spleen wei
Slide 25: SLN124 Summary
SLN124 Summary • Preclinical package: Robust data generated in several disease models. • Status: Several Clinical Trial Applications approved for first protocol, since halted. CTAs for new protocol being submitted soon. Interim data expected in H1 2021. • Clinical plans: Phase Ib in patients (β-Thal
Slide 26: SLN500 for the treatment of Complement-Mediated Diseases
SLN500 for the treatment of Complement-Mediated Diseases 26
Slide 27: Complement as a Target Cascade
Complement as a Target Cascade C3 - Hub of the complement cascade >Complement belongs to the innate immune system >Over 30 serum proteins SLN500 >Three pathways converge to form C3 convertases >Function: MAC formation and immune cell activation >Eculizumab (anti-C5 Ab): First FDA-approved drug for c
Slide 28: Attractive Market Size: Combined Opportunity in Multiple Orphan Indications
Attractive Market Size Combined Opportunity in Multiple Orphan Indications C3G C3 Glomerulopathy Est. combined prevalence US EU Antineutrophil Cytoplasmic ~5-15K Autoantibodies - Associated ANCA-AV patients PNH Paroxysmal Nocturnal Vasculitis ~30-150K Hemoglobinuria ~10-15K patients patients Atypica
Slide 29: SLN500 Proof of Mechanism Data
SLN500 Proof of Mechanism Data Dose response study with SLN500 in healthy mice 1.5 > Study design: d-3 d0 d7 d14 d21 d28 RNA DAY 28 C3/actb mRNA relat. to PBS 1.0 0.5 Serum siRNA serum serum serum Tissue BL sc (liver) 0.0 serum PBS 5 mg/kg 3 mg/kg 1 mg/kg 0.3 mg/kg 150 % remaining serum C3 PROTEIN T
Slide 30: SLN500 Summary
SLN500 Summary Rationale > Activation of the complement system is a pathologic feature of several diseases (such as C3 glomerulopathy, paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome and myasthenia gravis) > Mutations and/or deficiencies in complement regulating factors or st
Slide 31: Silence Therapeutics - Summary
Silence Therapeutics - Summary > Reproducible, proprietary gene silencing (RNAi) therapeutics platform, rapidly generating Valuable Platform internal pipeline and out-licensing options. Platform validated through collaborations with HQ in London AstraZeneca, Mallinckrodt and Takeda > SLN360 (CVD wit
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