Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — Cowen Healthcare Conference 2020
35 slides from Silence Therapeutics's conference presentation, Mar 2, 2020
Slide 1: Silence Therapeutics Cowen Healthcare Conference
Silence Therapeutics Cowen Healthcare Conference March 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 information and may Safe Harbour statement: this presentation may contain forward-looking statements that reflect the Company’s current views not be reproduced, further distributed to
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 Mallinckrodt and Takeda > SLN124 (β-Thalassemia and MD
Slide 4: 2019 Accomplishments & 2020 Outlook
2019 Accomplishments & 2020 Outlook 2019 2020 SLN124 Strengthened team SLN124 People Phase Ib CTA filed. Management team First patient dosed Recruitment of new CEO Several sites open and strengthened with several expected in Q1 2020. ongoing. recruiting. new hires, including Giles On track to report
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: Experienced Broader Management Team
Experienced Broader Management Team Head of Manufacturing Head of HR Head of BD General Counsel Jorgen Wittendorff Linnea Elrington John Strafford Barbara Ruskin > Over 25 years’ experience in the > Experienced HR professional. > Broad experience in biotech, > GC and Chief Patent Officer development
Slide 7: 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 8: 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 N o r m a lis e d ta r g e t m R N A specificity”. N o r m
Slide 9: 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 10: Development Pipeline
Development Pipeline © Silence Therapeutics 2020 10
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: SLN124 Iron Overload Disorders
SLN124 for the treatment of Iron Overload Disorders © Silence Therapeutics 2020 12
Slide 13: 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 14: 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 15: 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 16: SLN124 Ameliorates Splenomegaly and Improves Anemia in b-Thalassemic Mice
SLN124 Ameliorates Splenomegaly and Improves Anemia in b- 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 17: SLN124 Reduces Liver Iron Levels and Restores Normal Spleen Architecture in b-Thalassemic Mice
SLN124 Reduces Liver Iron Levels and Restores Normal Spleen Architecture in b-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,
Slide 18: Multicentre, Randomized, Placebo Controlled Phase Ib in 2020
Multicentre, Randomized, Placebo Controlled Phase Ib in 2020 This is a two part first-in-human, multicenter, randomized placebo controlled single ascending and multiple dose study to assess the preliminary safety, tolerability, PK and efficacy of SLN124 administered subcutaneously for the treatment
Slide 19: SLN124 Summary
SLN124 Summary • Preclinical package: Robust data generated in several disease models. • Status: Clinical Trial Application approved in UK (MHRA), Bulgaria (BDA), Germany (BfArM) and Turkey. First patients expected to enter a Phase Ib study in Q1 2020. Orphan Designation granted for β-Thalassemia. •
Slide 20: 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 20
Slide 21: 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 22: Lp(a) Distribution in the Population
Lp(a) Distribution in the Population Most biological entities Lp(a) distribution is skewed show a normal distribution with 20% of the population in a population with higher than 50 mg/dL Nordestgaard B Eur Heart J: 2010 31:2844 © Silence Therapeutics 2020 22
Slide 23: 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. • A risk ratio of 2 is double the Mortality risk. •1.2 to • A risk of 0.5 is half the risk 1.4 Ischemic Myocardial Stroke Infarction •1.2 to •2 to 3
Slide 24: 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 25: 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 26: 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 27: Compliance in Cardiovascular Disease
Compliance in Cardiovascular Disease Compliance and Statins ➢ Patients with ASCVD who stop taking statins are 50% more likely to die over a 2-3 year period than those that are compliant1 Compliance and Intensity of Treatment ➢ Outcome variable compositive endpoints of CV death or hospitalization for
Slide 28: 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 29: SLN500 for the treatment of Complement-Mediated Diseases
SLN500 for the treatment of Complement-Mediated Diseases 29
Slide 30: 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 31: 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 32: 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 PROTEIN TIME COURSE 150 % remainin
Slide 33: 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 34: 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 Mallinckrodt and Takeda > SLN124 (β-Thalassemia and MD
Slide 35: © Silence Therapeutics 2020
© Silence Therapeutics 2020 35
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