Silence Therapeutics PLC · NASDAQ:SLN
Silence Therapeutics — Investor Day (September 2019)
134 slides from Silence Therapeutics's investor day presentation, Sep 12, 2019
Slide 1: Silence Therapeutics R&D Day
Silence Therapeutics R&D Day September 12 2019
Slide 2: Disclaimer
Disclaimer The information contained in this presentation is being supplied and communicated to you on Safe Harbour statement: this presentation may contain forward-looking statements that reflect the a confidential basis solely for your information and may not be reproduced, further distributed to
Slide 3: Welcome and Agenda
Welcome and Agenda > Welcome and Introduction 8:00 > Coffee break 10:00 • Dr. David Horn Solomon, Chief Executive Officer > Elevated Lp(a) and > 2019 Half Year Results 8:30 Cardiovascular Disease 10:15 • Dr. Rob Quinn, Chief Financial Officer • Prof. Henry Ginsberg, Columbia University > Iron Loadin
Slide 4: Leadership Presenting Today
Leadership Presenting Today CEO Head R&D, CMO CFO David Horn Solomon Giles Campion Rob Quinn > Experienced public company > Former Chief Medical Officer > Chartered accountancy CEO, board member and and SVP R&D at Prosensa training at Deloitte before biotech investor (2009-2016), playing a major joi
Slide 5: Silence Therapeutics - Summary
Silence Therapeutics - Summary > Reproducible, proprietary gene silencing (RNAi) therapeutics platform, HQ in London Valuable rapidly generating internal pipeline and out-licensing options. Platform Platform validated through recently announced collaboration with Mallinckrodt Growing > SLN124 (β-Tha
Slide 6: 2019 – Year-to-Date Accomplishments
2019 – Year-to-Date Accomplishments R&D Highlights > SLN124 Clinical Trial Application filed in March 2019 with first patient dosed expected in H2 2019 > SLN124 granted Orphan Drug Designation in January by the European Medicines Agency for the treatment of β-Thalassemia > SLN360 entered IND-enablin
Slide 7: Experienced Management Team
Experienced Management Team Head of Manufacturing Head of HR Head of BD General Counsel Head of Technology Jorgen Wittendorff Linnea Elrington John Strafford Barbara Ruskin Marie W Lindholm > Joining in Oct 2019 > Experienced HR > Broad experience in > GC and Chief > Over 10 years in oligo professio
Slide 8: Strong Board, Augmented by Recent Additions
Strong Board, Augmented by Recent Additions Chief Executive Officer Non-Executive Chairman Non-Executive Director Dr. David Horn Solomon Iain Ross Dr. Steven Romano Non-Executive Director Non-Executive Director Non-Executive Director Alistair Gray Dave Lemus James Ede-Golightly © Silence Therapeutic
Slide 9: GalNAc-siRNA for Treatment of Disease
GalNAc-siRNA for Treatment of Disease Extracellular Intracellular Endosomal escape Recognition & binding GalNAc- siRNA Recycling ASGPR Receptors AAA (ASGPR) RNAi RISC AAA Target mRNA silencing Liver-specific and long lasting siRNA activity after internalization of GalNAc conjugate © Silence Therapeu
Slide 10: Reproducibly Silencing Disease-Associated Genes Using our Proprietary Platform Technology
Reproducibly Silencing Disease-Associated Genes Using our Proprietary Platform Technology Platform delivery technology; Target 1 Target 2 GalNAc-siRNA able to mediate highly specific gene silencing in hepatocytes N o r m a lis e d ta r g e t m R N A N o r m a lis e d ta r g e t m R N A (liver) – “Sp
Slide 11: 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 compositi
Slide 12: Development Pipeline
Development Pipeline © Silence Therapeutics 2019 12
Slide 13: SLN124 for the Treatment of Iron Overload Disorders
SLN124 for the treatment of Iron Overload Disorders © Silence Therapeutics 2019
Slide 14: Market Opportunity of SLN124
Market Opportunity of SLN124 US and EU patients Standard of Care β-Thalassemia ~40,000 TDT1 ~20,000 NTDT2 MDS3 >100,000 Benefits of SLN124 Advantages v Competition SLN124 aims to: Quality of Life SoC: Transfusions + Chelators 1. Reduce organ iron levels & Safety Antisense RNA 2. Enhance erythropoies
Slide 15: SLN124 Mechanism of Action: Increasing Hepcidin by Silencing its Repressor TMPRSS6
SLN124 Mechanism of Action: Increasing Hepcidin by Silencing its Repressor TMPRSS6 HJV BMPR Macrophages BMP > TMPRSS6 (Transmembrane Protease Serine 6) is a Ferroportin negative regulator of the P BMP/SMAD signaling TMPRSS6 Fe pathway P SMAD Iron recycling > Inhibition of TMPRSS6 in hepatocytes indu
Slide 16: Therapeutic Activity of SLN124 - Hereditary Hemochromatosis Model
Therapeutic Activity of SLN124 - Disease Model of Hereditary Hemochromatosis (HFE-/- mice) Collaboration with Study design d1 wk 3 Prof. Dr. Martina Muckenthaler Heidelberg University, Germany SC, n=6-7 HFE-/- mice, 1 mg/kg or 3 mg/kg TMPRSS6 mRNA (liver) Hepcidin (serum) Iron (serum) 2 .0 800 p<0.0
Slide 17: SLN124 Reduces ROS and Improves RBC Parameters in a β-Thalassemia Model
SLN124 Reduces ROS and Improves RBC Parameters in a 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, 3mg/kg Reactive oxygen species (ROS) Reticulocyte proportion Hematocrit
Slide 18: SLN360 for the Treatment of Cardiovascular Disease with High Lp(a)
SLN360 for the treatment of Cardiovascular Disease with High Lp(a) © Silence Therapeutics 2019
Slide 19: SLN360 Targets Lp(a) - an Independent Risk Factor for Cardiovascular Disease
SLN360 Targets Lp(a) - an Independent Risk Factor for Cardiovascular Disease Increased MI Risk with increased Lp(a) Lp(a) levels are genetically determined Recognized as a major untreated risk factor in cardiovascular disease Lp(a) levels are not significantly modifiable through diet or approved pha
Slide 20: Serum Lp(a) reduction: Proof of Mechanism Achieved
Proof of Mechanism Achieved Serial serum collection 1 5 0 L p (a ) d7 d14 le v e ls ± S D ) d-15 d0 d63 Serum Lp(a) reduction C o n tro l s e ru m 1 0 0 3 m g /k g Serum baseline 9 m g /k g siRNA sc N o r m a lis e d B L 3 x 3 m g /k g 5 0 Group mg/kg Days (M e a n 1 0 0 9 0 % R e d u c tio n 2 3 1
Slide 21: SLN500 for the Treatment of Complement-Mediated Diseases
SLN500 for the treatment of Complement -Mediated Diseases © Silence Therapeutics 2019
Slide 22: GalNAc siRNAs for the Treatment of Complement-Mediated Diseases
GalNAc siRNAs for the Treatment of Complement-Mediated Diseases Schematic overview - complement system Targeting the complement system offers a broad indication spectrum (such as Paroxysmal Nocturnal Hemoglobinuria, Myasthenia gravis, C3 Glomerulopathy, atypical Hemolytic Uremic Syndrome or Cold Agg
Slide 23: SLN500 - Proof of Mechanism in Vivo
SLN500 - Proof of Mechanism in Vivo d-3 d0 d4 d10 d14 Study design: > n=4 healthy mice per group, serum sampling at day -3, 4, 10 and 14, liver tissue at day 14 > siRNAs: non-optimized GalNac conjugated chemistry Serum baseline siRNA serum serum Tissue collection (liver) sc Final serum 120 Sequence
Slide 24: Expected Newsflow & Company Milestones
Expected Newsflow & Company Milestones H1 2019 H2 2019 2020 SLN124 File CTA First In Human Dosing First Interim Results SLN360 Clinical candidate nomination IND/CTA filing SLN500 Clinical candidate nomination IND-enabling studies Quark Out-License in QPI-1002 Potential release of DGF Phase 3 results
Slide 25: Financial Update
R&D Day, September 12 2019 Financial Update Dr. Rob Quinn Chief Financial Officer
Slide 26: Agenda
Agenda 1. Corporate overview 2. H1 2019 Results 3. Partnered programs 4. Outlook © Silence Therapeutics 2019 26
Slide 27: Corporate Overview
Corporate Overview > Silence Therapeutics (SLN.L) is listed on the AIM sub-market of the London Stock Exchange > The company was formed in 2005 through the reverse merger of Atugen AG with AIM-listed SR Pharma. Through the Atugen legacy we have over 18 years’ experience in siRNA and some of the foun
Slide 28: H1 2019 Results
H1 2019 Results Financial Results ($USm) H1 2019 H1 2018 FY 2018 Revenue – – – R&D costs (6.1) (6.4) (11.9) G&A costs (5.7) (5.7) (13.2) Operating loss (11.8) (12.1) (25.1) Other income 0.1 0.1 0.1 Tax 1.7 1.4 2.5 Loss after tax (10.0) (10.6) (22.5) Cash & cash equivalents1 20.1 41.9 32.3 Converted
Slide 29: Collaboration with Mallinckrodt Pharmaceuticals for Complement-Mediated Diseases
Collaboration with Mallinckrodt Pharmaceuticals for Complement-Mediated Diseases Summary of Terms > Agreement provides Mallinckrodt with exclusive worldwide license for Silence’s $20M Upfront C3 complement asset (SLN500), with Up to $10M in research milestones options to license up to two additional
Slide 30: Out-Licenses: Alnylam and Quark
Out-Licenses: Alnylam and Quark Alnylam Pharmaceuticals > Settlement and license agreement in Dec 2018 > Tiered royalty of 0.33%-1% on EU sales of ONPATTRO® through 2023. All legal proceedings resolved > First royalties expected to be received in Q4 2019 Quark Pharmaceuticals > Out-licensed oligo ch
Slide 31: Outlook
Outlook SLN124 > SLN124 Phase Ib commences soon with interim results for the Part A (Single Ascending Dose) expected in 2020 > Phase Ib trial is expected to fully readout in H2 2021 SLN360 > IND and/or CTA expected to be filed in H2 2020 > Phase I trial to start shortly thereafter and funding this p
Slide 32: Iron Loading Anemias - β-Thalassemia and Myelodysplastic Syndromes
R&D Day, September 12 2019 Iron Loading Anemias - β-Thalassemia and Myelodysplastic Syndromes Prof John Porter University College London Hospital Red Cell Disorders Unit © Silence Therapeutics 2019
Slide 33: Thalassemia Etiology
Thalassemia Etiology A group of anemias resulting from imbalanced globin chain synthesis Secondary to reduced synthesis of α or β globin Excess of the unaffected globin leads to precipitation in: red cells (hemolysis) bone marrow (ineffective erythropoiesis) Adult hemoglobin Genetic basis β-Thalasse
Slide 34: β-Thalassemia
β-Thalassemia 34
Slide 35: β-Thalassemia Pathophysiology
β-Thalassemia Pathophysiology Decreased β globin synthesis Unpaired α globin Splenomegaly Hemolysis Ineffective erythropoiesis Transfusion Anemia Erythropoietin Erythroid marrow Skeletal expansion deformities, osteopenia Iron overload 35
Slide 36: Spectrum of Thalassemias
Spectrum of Thalassemias Non-transfusion-dependent Transfusion-dependent Transfusions Occasional Intermittent Regular, lifelong seldom required transfusions transfusions required transfusions required required α-Thalassemia trait Mild HbE/β-Thalassemia Mild homozygous B+/B+ β-Thalassemia major (TDT)
Slide 37: Ineffective Erythropoiesis Drives Morbidities of Untransfused β-Thalassemias
Ineffective Erythropoiesis is Integral to a Vicious Cycle Driving Morbidities of Untransfused β-Thalassemias (NTDT) Pathophysiology of β- Morbidities Thalassemia Chronic Detrimental effects on growth, organ and hemolytic vascular function, anemia gall stones Hemichromes Hemolytic and ROS anemia and
Slide 38: Iron Overload in NTDT and TDT
Iron Overload in NTDT and TDT Hypogonadotrophic Hypogonadism 20–40 mg /day (0.3–0.6 mg/kg/day) Hypothyroidism Erythron Transfusion Hypoparathyroidism Erythron Cardiac siderosis heart failure Erythroferrone Hepatic failure 20mg/day carcinoma Diabetes mellitus Rt Red Transferrin Macrophages NTBI 1-2mg
Slide 39: Transfusion Intensity Reflects Underlying Severity and Secondary Morbidities
Transfusion Intensity Reflects the Underlying Severity and Contributes to Secondary Morbidities NTDT TDT Non-Transfusion Dependent β-Thalassemia Transfusion Dependent β-Thalassemia Spectrum of Severity and transfusion dependence > Transfused sporadically (e.g. growth failure, > Regular lifelong tran
Slide 40: Therapeutic Options in Transfusion-Dependent β-Thalassemia
Therapeutic Options in Transfusion-Dependent β−Thalassemia Non curative >Transfusion and chelation >Pharmacological enhancers of effective erythropoiesis Curative >Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) >Gene therapies 40
Slide 41: Improving Survival in Birth Cohorts of TM Patients
Improving Survival in Birth Cohorts of TM Patients UK registry (N=736) UCLH, UK (N=103) 1.00 1.00 1975-97 (n=42) Survival probability 1975-1984 Survival probability 0.75 0.75 1965-74 (n=39) 1965-1974 1955-64 (n=21) 0.50 1955-1964 0.50 0.25 0.25 Before 1955 Analysis September 2000 0 0 0 5 10 15 20 25
Slide 42: Decline in Co-Morbidities in TDT with Introduction of Iron Chelation
Decline in Co-Morbidities in TDT with Introduction of Iron Chelation Patients with β-thalassemia major born after 1960 (N = 977) Birth 1970–1974* Birth 1980–1984† Death at 20 years 6.3% 1% Hypogonadism 64.5% 14.3% Diabetes 15.5% 0.8% Hypothyroidism 16.7% 4.9% *DFO i.m., 1975; †DFO s.c., 1980. In 199
Slide 43: Co-Morbidities in Transfusion-Dependent Thalassemia at UCLH
Co-Morbidities in Transfusion-Dependent Thalassemia (TDT) (%) at UCLH 2015 1999 Cardiac iron high 4 10 (T2*<10ms) Cardiac iron moderate 15 47 (T2* 15-20ms) LIC badly controlled 12.8 25 > 15mg/g dry wt (%) age < 40 yo age > 40yo Diabetes (%) 10 24 insulin dependent Hypoparathyroidism (%) 3 13 Hypothy
Slide 44: Unmet Need – Issues With Standard Thalassemia Management
Unmet Need – Issues With Standard Thalassemia Management High global prevalence of thalassemias >global birth rate 50-60,000 pa >global prevalence of 288,000 for severe β-thalassemia Issues of delivery and adherence to transfusion + chelation >Only 12% of children with TDT globally receive adequate
Slide 45: Targeting Ineffective Erythropoiesis in Thalassemias
Targeting Ineffective Erythropoiesis (IE) in Thalassemias Possible benefits of reduced IE1 Globin Chain > Improved anemia Imbalance > Reduced spleen & extramedullary expansion > Indirect increase in serum hepcidin EPO > Improved QOL Approaches > Stimulation of proliferation (Epo) > Decreased globin
Slide 46: Myelodysplastic Syndromes
Myelodysplastic Syndromes
Slide 47: What are Myelodysplastic Syndromes (MDS)?
What are Myelodysplastic Syndromes (MDS)? A spectrum of myeloid clonal disorders > Worldwide incidence ~5 per 100,000 > Median age at onset is in the range 65–70 years2 Occurrence: > De novo (primary MDS) > Secondary or treatment-related MDS Significant morbidity and mortality due to: > Cytopenias –
Slide 48: IPSS-R Prognostic Risk Category Clinical Outcomes
IPSS-R (Revised) Prognostic Risk Category Clinical Outcomes* Categorizes patients into 1 of 5 groups, based on risk of mortality and AML transformation > Composite Scoring system from 0 to 4 > Categories: cytogenetics, bone marrow blast %, Hemoglobin, Platelets, Absolute neutrophil count No. patient
Slide 49: MDS Etiology and Progression to AML
Myelodysplastic Syndromes Etiology and of Progression to AML Altered immune response Altered Altered marrow stroma cytokine response Radiation Oxidative Increased apoptosis stress Clonal Stem cell Clonal Age myelo- AML mutation evolution poiesis Ineffective T-cell haemopoiesis attack Chemicals Addit
Slide 50: In MDS, Iron Overload Contributes to Ineffective Erythropoiesis
In MDS, Iron Overload Contributes to Ineffective Erythropoiesis, Stromal Dysfunction and Genetic Instability In addition to its negative impact on erythropoiesis, iron overload aggravates oxidative stress and causes stromal dysfunction, potentially leading to faster clonal evolution towards leukemia
Slide 51: Treatment Options in MDS
Treatment Options in MDS Lower risk (IPSS Low, Int-1) Higher risk (IPSS Int-2, High) • EPO (ESAs) ± G-CSF • Allo-SCT • Immunosuppression • HMAs: 5-azacitidine, decitabine – ATG ± cyclosporin • Lenalidomide – del(5q) • Intensive chemotherapy • HMAs: 5-azacitidine, decitabine • Transfusion + Iron chel
Slide 52: Therapeutic Priorities in Low vs High Risk MDS
Therapeutic Priorities in Low vs High Risk MDS Platzbecker, Blood 2019 52
Slide 53: Unmet Need in MDS
Unmet Need in MDS Limitations of ESAs & lenalidomide >High refractory rate >Only small subset of patients eligible Limitations of iron chelators >Adherence major issue - older population with polypharmacy/ low tolerance for side-effects Anemia – a major clinical challenge >Anemia & transfusion depen
Slide 54: Hepcidin-Ferroportin Axis Competitor Overview
Competitor Overview Product Company Highest Indications MOA Modality Administration Phase Luspatercept Celgene Registration 2L MDS – Reg Erythroid Fusion protein SC, every 21 (Acceleron) TDT – Reg maturation days EMA 1L MDS – Ph3 agent – TGFβ NTDT – Ph2 ligand trap LJPC-401 La Jolla Phase 2 Cardiac
Slide 55: Summary of Clinical Stage Competitors
Summary of Clinical Stage Competitors Luspatercept > Launch expected in early 2020 in transfusion dependent β-Thalassemia and first-line MDS; expansion expected to NTDT (ongoing Phase 2) and second-line MDS (ongoing Phase 3) > Majority of patients (60-80%) missed primary endpoint in Ph3s; potential
Slide 56: Hepcidin, Iron Balance and Erythropoiesis
Hepcidin, Iron Balance and Erythropoiesis
Slide 57: Hepcidin – The Regulator of Plasma Iron
Hepcidin – The Regulator of Plasma Iron SLN124 TMPRSS6 > Hepatic-derived primary regulator of iron homeostasis > Controls plasma iron by regulating • intestinal absorption • iron recycling from macrophages > Hepcidin deficiency leads to iron toxicity/iron overload • Iron loading anemias – inherited
Slide 58: Iron Restriction as a Therapeutic Tool?
Iron Restriction as a Therapeutic Tool? Iron restriction is a physiological Iron restriction by adaptation in anemia of chronic TMPRSS6 inhibitors disease • Gene ablation, siRNA or ASO • Hepcidin induced reduction in techniques inhibit TMPRSS6 transferrin saturation expression to stimulate • Iron re
Slide 59: Persistent Ineffective Erythropoiesis Suppresses Hepcidin
Persistent Ineffective Erythropoiesis Suppresses Hepcidin to Promote Iron Toxicity and Anemia Mature red blood Erythroblasts cells (RBC) Physiological state EPO ERFE HBB mutation (β-thal) Fe HSC mutations (MDS) Hepcidin ROS (OH●) Iron loading Hypoxia APOPTOSIS anemias Anemia & β-Thalassemia EPO MDS
Slide 60: SLN124: TMPRSS6 as a Target for Drug Action
SLN124: TMPRSS6 as a Target for Drug Action
Slide 61: Rationale for Targeting TMPRSS6 in Iron Overload Disorders
Rationale for Targeting TMPRSS6 in Iron Overload Disorders SLN124 > Hepcidin is the master regulator of iron homeostasis TMPRSS6 • Reduces dietary iron absorption and HJV BMP controls release of iron from storage cells HFE BMPR • Hepcidin levels are low in patients P with iron-loading anemias > TMPR
Slide 62: Loss of TMPRSS6 is Well Characterized in Animal Models
Loss of TMPRSS6 is Well Characterized in Animal Models In iron-loading conditions >Ablation of TMPRSS6 expression in murine models for β-Thalassemia or hereditary hemochromatosis1,2 • Improves hematopoiesis, ameliorates anemia, corrects splenomegaly • Normalizes transferrin saturation, corrects iron
Slide 63: Relevant Animal Disease Models for Iron-Loading Anemia
Relevant Animal Disease Models to Study Iron-Loading Anemia and Hepcidin Deficiency β-Thalassemia intermedia > Hbbth3/+ mice > Beta globin gene defect causes β-Thalassemia Collaboration with > Prototypical iron-loading anemia with Dr. J. Vadolas & Dr. G. Grigoriadis 2° hepcidin deficiency Monash Med
Slide 64: SLN124 in Non-Clinical Models
SLN124 in Non-Clinical Models 64
Slide 65: SLN124 Reduces Transferrin Saturation in β-Thalassemic Mice
SLN124 Reduces Transferrin Saturation in β-Thalassemic Mice Study design Collaboration with Hbbth3/+ mice, 2-4 m, n=5-8 d1 wk 2 wk 5 Dr. J. Vadolas & Dr. G. Grigoriadis 2x 3mg/kg SLN124 s.c. 1.25 mg/ml deferiprone in drinking water Monash Medical Centre/Melbourne, Australia TMPRSS6 mRNA (liver) Hepc
Slide 66: SLN124 Reduces ROS, Improves RBC Maturation in β-Thalassemic Mice
SLN124 Reduces ROS, Improves RBC Maturation and Raises RBC Count in Circulation in β-Thalassemic Mice Study design Collaboration with Hbbth3/+ mice, 2-4 m, n=5-8 d1 wk 2 wk 5 Dr. J. Vadolas & Dr. G. Grigoriadis 2x 3mg/kg SLN124 s.c. 1.25 mg/ml deferiprone in drinking water Monash Medical Centre/Melb
Slide 67: SLN124 Ameliorates Splenomegaly and Improves Anemia in 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 Dr. J. Vadolas & Dr. G. Grigoriadis 2x 3mg/kg SLN124 s.c. 1.25 mg/ml deferiprone in drinking water Monash Medical Centre/Melbourne, Australia Spleen weig
Slide 68: SLN124 Reduces Liver Iron Levels and Restores Spleen Architecture
SLN124 Reduces Liver Iron Levels and Restores Normal Spleen Architecture in β-Thalassemic Mice Study design Collaboration with Hbbth3/+ mice, 2-4 m, n=5-8 d1 wk 2 wk 5 Dr. J. Vadolas & Dr. G. Grigoriadis 2x 3mg/kg SLN124 s.c. 1.25 mg/ml deferiprone in drinking water Monash Medical Centre/Melbourne,
Slide 69: SLN124 Enhances Tissue Iron Reduction by Deferiprone in Hemochromatosis Model
In a Hereditary Hemochromatosis model with Established Iron Overload, SLN124 Enhances Reduction of Tissue Iron Levels by Deferiprone Study design d1 wk 3 wk 6 Collaboration with HFE-/- mice, females, 3 m, n=8 Prof. Dr. Martina Muckenthaler 1 or 2x 3mg/kg SLN124 s.c. +/- 0.5 mg/mL DFP in drinking wat
Slide 70: Summary
Summary > β thalassemia and MDS are both marked by anemia characterized by ineffective erythropoiesis and increased iron-loading > Although these diseases have distinct etiologies and affect different patient populations both display dyserythropoiesis and dysregulation of iron metabolism through low
Slide 71: SLN124 for the Treatment of Iron Loading Anemias
R&D Day, September 12 2019 SLN124 for the Treatment of Iron Loading Anemias Dr Giles Campion Head of R&D, Chief Medical Officer
Slide 72: SLN124 – Molecular Design
SLN124 – Molecular Design Chemical GalNAc (N-Acetyl modifications Galactosamine) Increase stability Mediates targeted delivery to hepatocytes Linker Target-specific siRNA Connects siRNA sense Mediates TMPRSS6 gene silencing strand to GalNAc GalNAc conjugation is becoming a well established strategy
Slide 73: TMPRSS6 is a Well-Validated Target in Humans
TMPRSS6 is a Well-Validated Target in Humans > Hepcidin key regulator of iron metabolism1 > In humans, loss-of-function mutations in TMPRSS6 gene cause iron-refractory iron deficiency anemia (IRIDA)2,3,4,5 • Symptoms more pronounced during childhood/adolescence • Generally normal growth and developm
Slide 74: Favorable Non-Clinical Safety Profile
Favorable Non-Clinical Safety Profile > 29-day GLP toxicology studies in mice and NHP - no observations of overt signs of toxicity at any dose level (NOAEL 83.3 mg/kg/week, highest dose tested) • Some events considered platform-wide toxicological responses for GalNAc-siRNA conjugates independent of
Slide 75: Potential Significant Benefits of SLN124
Potential Significant Benefits of SLN124 Patient care Targets affected by SLN124 > Differentiated MoA to ↑ hepcidin SLN124 > Combination with chelators or ESAs > Provide much needed option Chelator for treating ESA failure ESA > Long duration of action: ≥ monthly s.c. dosing Improved safety over exi
Slide 76: SLN124 Potential to Address an Unmet Medical Need
SLN124 Has the Potential to Address an Unmet Medical Need by Improving Anemia and Restoring Iron Homeostasis SLN124 vs. approved therapies to treat chronic anemia and iron overload Therapy goal SLN124 RBC transfusion Iron chelators ESAsa Reduce systemic iron levelsb +/- Improve erythropoiesisb +/- A
Slide 77: Phase Ib Clinical Trial Overview – SLN124
Phase Ib Clinical Trial Overview – SLN124 2-part first-in-human, single-blind, multicenter, randomized placebo-controlled single ascending and multiple dose study to assess the preliminary safety, tolerability, PD and PK of SLN124 administered subcutaneously for the treatment of Non-transfusion-depe
Slide 78: Phase Ib Study Parts A and B – SLN124
Phase Ib Study Parts A and B – SLN124 PART A (Non-transfusion-dependent β-Thalassemia patients) PART B 0.3 mg/kg TBD mg/kg Cohort 1 (x3 dose) 1.0 mg/kg n=8 (6A+2P) Cohort 5 Cohort 2 NTDT 3.0 mg/kg n = 15 n=8 (10A+5P) (6A+2P) Cohort 3 NTDT NTDT 10.0 mg/kg n=8 (6A+2P) Cohort 4 TBD mg/kg NTDT n=8 X.X m
Slide 79: Phase Ib Study Objectives – SLN124
Phase Ib Study Objectives – SLN124 > Safety and tolerability > Pharmacokinetics > Determine impact of single and multiple doses of SLN124 on pharmacodynamic and clinical markers of efficacy • Serum Fe • Ferritin • Transferrin Iron overload • Transferrin Saturation (Tsat) • Non-transferrin bound iron
Slide 80: Phase Ib Patient Population – SLN124
Phase Ib Patient Population – SLN124 > Patients selected vs. Healthy Volunteers (HV) due to the risk of causing anemia in HVs through SLN124 MoA > Patients with NTD β-Thalassemia and low/very low risk MDS with clear evidence of biochemical iron overloading > NTD β-Thalassemia selected with no or lim
Slide 81: Phase Ib Inclusion Criteria – SLN124
Phase Ib Inclusion Criteria – SLN124 Evidence of biochemical iron overload and anemia > Tsat, ferritin, hemoglobin • Mean ferritin level > 300 µg/L • Transferrin saturation > 45% • Mean Hb 10 g/L >Stable chelator use permitted © Silence Therapeutics 2019 81
Slide 82: SLN124 European Regulatory Interactions
SLN124 European Regulatory Interactions Scientific advice > Clinical and Quality with MHRA - June 2018 and January 2019 > Quality with BfArM - December 2018 EU orphan drug designation for β-Thalassemia > Decision adopted for SLN124 - January 2019 First-in-human trial of SLN124 in MDS and β-Thalassem
Slide 83: SLN124 Summary
SLN124 Summary Hepcidin deficiency - key pathophysiological mechanism linking anemia and iron overload in β-Thalassemia and MDS > Differentiated MoA specifically targeting key iron regulator - hepcidin > Robust Hb response in prototypical model of ineffective erythropoiesis > Consistent ↓ in plasma
Slide 84: Questions & Answers
R&D Day, September 12 2019 Questions & Answers
Slide 85: Elevated Lp(a) and Cardiovascular Disease
R&D Day, September 12 2019 Elevated Lp(a) and Cardiovascular Disease Henry Ginsberg MD Irving Professor of Medicine Vagelos College of Physicians and Surgeons Columbia University © Silence Therapeutics 2019
Slide 86: Lowering LDL has Transformed the Natural History of ASCVD
Lowering LDL has Transformed the Natural History of Atherosclerotic Cardiovascular Disease The Lancet 376 (9753)1670 © Silence Therapeutics 2019 86
Slide 87: Rates of ASCVD Remain Elevated Even After Lowering LDL-C
However, Rates of ASCVD Remain Elevated in High-Risk Patients Even After Dramatic Lowering of LDL-C: Why? > Statin intolerance > Inadequate dosing > Inadequate use of combination therapies > Compliance © Silence Therapeutics 2019 87
Slide 88: What Can We Do?
What Can We Do? > Treat Statin Intolerance > Improve Compliance > Convince Doctors to Use Optimal Doses > Add second drugs: • Ezetimibe • PCSK9 Inhibitors But diminishing returns on LDL-C lowering and increasing problems regarding compliance © Silence Therapeutics 2019 88
Slide 89: There are Non-LDL-C Causes of ASCVD
More Importantly: There are Non-LDL-C Causes of ASCVD Residual risk > Hypertension > Smoking > Diabetes/Insulin Resistance > High Triglycerides > Low HDL-C > LIPOPROTEIN (a) © Silence Therapeutics 2019 89
Slide 90: Lipoprotein(a)
Lipoprotein(a) KIV-2 copy number variant: > 2 to >40 repeats LDL-like apo(a) particle Koschinsky et al. Curr Opin Lipidol, 2004;15:167-174 © Silence Therapeutics 2019 90
Slide 91: Lipoprotein(a)
Lipoprotein(a) Lp(a) is an LDL-like particle covalently bound to a glycoprotein, apo(a), through a single disulfide bond Kringle IV type 2 repeat: Non-HDL Cholesterol 114 AA (5.6kb)/repeat Chylomicrons Very low density Lipoproteins Intermediate density Lipoproteins Lipoprotein (a) [Lp(a)] is a circu
Slide 92: 1963: Geneticist Kare Berg
1963: Geneticist Kare Berg > Goal: define lipoprotein differences between individual human sera. > Discovery: Through immunological investigations of human serum he discovered a new antigen that was associated with low density lipoproteins (LDL). He shortly showed that this new antigen was a genetic
Slide 93: Structural Homology Between PLG and Apo(a)
Schematic Illustration of the Structural Homology Between PLG and Apo(a) Konrad Schmidt et al. J. Lipid Res. 2016;57:1339-1359 © Silence Therapeutics 2019 93
Slide 94: Lp(a): Particle Heterogeneity
Lp(a): Particle Heterogeneity Tsimikas, JACC, 2017, 69:692 © Silence Therapeutics 2019 94
Slide 95: Copenhagen General Population Lp(a) Distribution
Copenhagen General Population (n=6000) Men Women Fraction of Population 20% 20% 0 50 100 150 200 0 50 100 150 200 Lp(a), mg/dL Lp(a), mg/dL Nordestgaard B Eur Heart J: 2010 31:2844-53. © Silence Therapeutics 2019 95
Slide 96: © Silence Therapeutics 2019
© Silence Therapeutics 2019 96
Slide 97: Lp(a) Levels are About 90% Genetically Determined
Copenhagen General Population (n=6000) Lp(a) Levels are About 90% Genetically Determined Men Women High number of Kringle IV-2 repeats Fraction of Population Low number of Kringle IV-2 repeats 20% 20% 0 50 100 150 200 0 50 100 150 200 Lp(a), mg/dL Lp(a), mg/dL Nordestgaard et al, EHJ, 2010, 31:2844
Slide 98: Prevalence of Elevated Lp(a): US and Globally
Prevalence of Elevated Lp(a): US and Globally Prevalence 20% 10% 5% 1% Lp(a) Level 60 mg/dL 90 mg/dL 116 mg/dL 180 mg/dL Number (USA) 64 million 30 million 16 million 3.2 million Number (EU) 150 million 75 million 37.5 million 7.5 million Number Globally 1.4 billion 700 million 350 million 7 million
Slide 99: Nonfatal MI and Coronary Death (9318 Cases)
Nonfatal MI and Coronary Death (9318 Cases) Emerging Risk Factor Collaboration. JAMA 2009; 302: 412-23 MI = Myocardial infarction © Silence Therapeutics 2019 99
Slide 100: Risk of MI as a Function of Lp(a) Levels
Risk of MI as a Function of Lp(a) Levels in the General Population: Copenhagen City Heart Study Kamstrup et al. JAMA 2009; 301: 2331-9 © Silence Therapeutics 2019 100
Slide 101: Ischemic Stroke (1890 Cases)
Ischemic Stroke (1890 Cases) Emerging Risk Factor Collaboration. JAMA 2009; 302: 412-23 © Silence Therapeutics 2019 101
Slide 102: Lp(a): a Genetically Validated Target
Lp(a): a Genetically Validated Target Kamstrup PR, et al. JAMA. 2009;301(22):2331-2339 © Silence Therapeutics 2019 102
Slide 103: Lp(a): a Genetically Validated Target
Lp(a): a Genetically Validated Target Nordestgaard and Langsted J. Lipid Res. 2016. 57: 1953–1975 © Silence Therapeutics 2019 103
Slide 104: Lp(a) and Aortic Stenosis
Lp(a) and Aortic Stenosis Lp(a) SNP rs10455872 Relative risk of aortic valve per allele Calcification 2.05 (1.63-2.57) Stenosis Sweden 1.68 (1.32-2.15) Stenosis Denmark 1.60 (1.12-2.28) © Silence Therapeutics 2019 104
Slide 105: Lp(a) and Aortic Stenosis
Lp(a) and Aortic Stenosis Nordestgaard and Langsted J. Lipid Res. 2016. 57: 1953–1975 © Silence Therapeutics 2019 105
Slide 106: Is There an Unmet Need to Treat Lp(a)?
>This is all very interesting but does it mean that there is an unmet need to treat Lp(a)? >Why not just treat LDL more aggressively? © Silence Therapeutics 2019 106
Slide 107: Statin Treatment and CV Risk of Lp(a)
Statin Treatment and CV Risk of Lp(a) Patient-level meta-analysis of placebo-controlled statin trials Lancet 2018; 392: 1311–20 © Silence Therapeutics 2019 107
Slide 108: Lp(a) Largely Poorly Managed by Current Therapies
Lp(a) Largely Poorly Managed by Current Therapies > No clinical trial investigating the effect of specifically lowering Lp(a) on prevention of CVD conducted so far – no specific guidelines for targeting Lp(a). > Cholesterol lowering drugs (e.g. statins etc) are used to reduce additional risk factors
Slide 109: Benefit of Reduction
Benefit of Reduction © Silence Therapeutics 2019
Slide 110: FOURIER Trial
FOURIER Trial >Elevated baseline Lp(a) concentration was independently associated with an increased risk of coronary events >Patients with elevated baseline Lp(a) levels derived greater absolute reduction in Lp(a) and tended to derive greater clinical benefit from PCSK9 inhibition >Clinical benefit
Slide 111: ODYSSEY Outcomes Trial
ODYSSEY Outcomes Trial >Baseline Lp(a) predicts MACE in patients with recent ACS. >The contribution of Lp(a) lowering to event reduction with alirocumab increases with higher baseline Lp(a) levels, and becomes clinically meaningful in patients with elevated baseline Lp(a) levels. © Silence Therapeut
Slide 112: Changes in Lp(a) and LDL-C With Equivalent Effects on CVD
Changes in Lp(a) and LDL-C With Equivalent Effects on CVD 1.0 mmol/L (39 mg/dl cholesterol) lifetime lower LDL-C 50% reduction in lifetime risk of CHD 0.4 - 101.5 mg/dl (30-40 mg/dl cholesterol) lifetime lower Lp(a) Burgess SB, Ference BA, et al. 2018; JAMA Cardiology doi: 10.1001/jamacardio.2018.14
Slide 113: Desired Profile of New Therapeutic to Lower Lp(a)
Desired Profile of New Therapeutic to Lower Lp(a) © Silence Therapeutics 2019
Slide 114: siRNA Knockdown: Serum Lp(a) Reduction
siRNA Knockdown Serial serum collection 1 5 0 L p (a ) le v e ls ± S D ) d-15 d0 d7 d14 d63 Serum Lp(a) reduction C o n tro l s e ru m 1 0 0 3 m g /k g Serum baseline 9 m g /k g siRNA sc N o r m a lis e d B L 3 x 3 m g /k g 5 0 Group mg/kg Days (M e a n 1 0 0 9 0 % R e d u c tio n 0 2 3 1 0 7 1 4 2
Slide 115: Summary
Summary >Elevated Lp(a) a potent risk factor for cardiovascular disease but is underappreciated in management guidelines >Usual life-style changes and currently approved therapeutics not effective >New agents required that lower Lp(a) by up to 80% >Compliance a potent factor in reducing the effectiv
Slide 116: SLN360 for the Treatment of Cardiovascular Disease Associated With High Lp(a)
R&D Day, September 12 2019 SLN360 for the Treatment of Cardiovascular Disease Associated With High Lp(a) Dr Giles Campion Head of R&D, Chief Medical Officer
Slide 117: Lp(a) as a Target for SLN360
Lp(a) as a Target for SLN360 The Lp(a) complex is composed of two different proteins encoded by the LPA and the APOB genes and a lipid particle, both expressed in hepatocytes: GalNAc siRNA LPA gene ApoB LDL-C The LPA gene product is dominant and rate limiting for the assembly of the atherogenic Lp(a
Slide 118: Lead and Lead Selection
Lead and Lead Selection Pharmacodynamic / Proof of Mechanism studies in vivo (NHP) Synthesis of Pre-clinical GalNAc- Development conjugated siRNA Potency in molecules human & cynomolgus 1° hepatocytes IND/CTA H2 2020 Design and screen of 250 siRNAs * There is no rodent homologue of LPA, in vivo test
Slide 119: Additional Lowering of ApoB
Additional Lowering of ApoB Lp(a) reduction leads to significant A p o B 1 2 5 lowering of the disease-relevant le v e ls ) 1 0 0 C o n tro l biomarker ApoB s e ru m PROTEIN 3 m g /k g 7 5 9 m g /k g B L > Dose-dependent reduction in ApoB N o r m a lis e d 5 0 3 x 3 m g /k g (M e a n 2 5 serum level
Slide 120: No Downregulation of Plasminogen mRNA
No Downregulation of Plasminogen mRNA 1.5 > Plasminogen protein has high homology to apo(a) (relative to UT) 1.0 PLG/ACTB Human > SLN360 sequence shows several In vitro 0.5 Cyno mismatches to PLG sequence In vitro 0.0 -12 -11 -10 -9 -8 -7 -6 > No dose-dependent alterations log [M] siRNA in PLG level
Slide 121: Clinical-Stage Competition – Amgen (Phase I)
Clinical-Stage Competition – Amgen (Phase I) 3x3mg/kg weekly doses > Amgen (Arrowhead molecule) Amgen/Arrowhead – GalNac siRNA > Amgen: peak inhibition D29-43 > SLN360: peak inhibition D17-21 90% > Amgen: 90% reduction at peak inhibition Melquist et al AHA 2016 Scientific Sessions > SLN360 >90% redu
Slide 122: Clinical-Stage Competitors Targeting Lp(a)
Clinical-Stage Competitors Targeting Lp(a) Correct as of Aug 2019 Product Company Highest Phase Indications MOA Modality Administration Arrowhead/ CVD with Apo(a) AMG-890 Phase I siRNA SC, N/A Amgen high Lp(a) inhibition AKCEA-apo(a)- Akcea Phase 2 CVD with Apo(a) SC, weekly Antisense LRx (TQJ230) (
Slide 123: SLN360 Summary
SLN360 Summary Rationale > Lp(a) is a low-density lipoprotein 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 no specific Lp(a) targeting therapy av
Slide 124: SLN500 for the Treatment of Complement-Mediated Diseases
R&D Day, September 12 2019 SLN500 for the Treatment of Complement-Mediated Diseases Dr Giles Campion Head of R&D, Chief Medical Officer
Slide 125: Complement as a Target Cascade
Complement as a Target Cascade C3 - Hub of the complement cascade > Complement belongs to the innate immune system > >30 serum proteins > Three pathways converge to form SLN500 C3 convertases > Function: MAC formation and immune cell activation > Eculizumab (anti-C5 Ab): First FDA-approved drug for
Slide 126: Attractive Market Size
Attractive market size Combined opportunity in multiple orphan indications C3G Est. combined prevalence C3 Glomerulopathy US EU ~5-15K Antineutrophil Cytoplasmic ANCA-AV patients PNH Paroxysmal Nocturnal Autoantibodies - Associated Vasculitis ~30-150K ~10-15K Hemoglobinuria patients patients aHUS Po
Slide 127: 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 RNA DAY 28 d21 d28 C3/actb mRNA relat. to PBS 1.0 0.5 Serum siRNA serum serum serum Tissue BL sc (liver) serum 0.0 PBS 5 mg/kg 3 mg/kg 1 mg/kg 0.3 mg/kg 150 Single ascending doses of PROT
Slide 128: Clinical Stage Drugs Targeting C3
Clinical Stage Drugs Targeting C3 Correct as of Aug 2019 Product Company Highest Phase Indications MOA Modality Administration Nephropathies Synthetic APL-2 Apellis Phase 3 (C3G), GA, PNH, C3 inhibition SQ, daily peptide CAD, WAHA C3G, PNH, SQ or IV, unclear periodontitis, Synthetic dosing but likel
Slide 129: 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 130: Questions & Answers
R&D Day, September 12 2019 Questions & Answers
Slide 131: Closing Remarks
R&D Day, September 12 2019 Closing Remarks Dr. David Horn Solomon Chief Executive Officer
Slide 132: Silence Therapeutics’ Summary
Silence Therapeutics’ Summary > Reproducible, proprietary gene silencing (RNAi) therapeutics platform, HQ in London Valuable rapidly generating internal pipeline and out-licensing options. Platform Platform validated through recently announced collaboration with Mallinckrodt Growing > SLN124 (β-Thal
Slide 133: Outlook
Outlook SLN124 > SLN124 Phase Ib commences soon with interim results for the Part A (Single Ascending Dose) expected in 2020 > Phase Ib trial is expected to fully readout in H2 2021 SLN360 > IND and/or CTA expected to be filed in H2 2020 > Phase I trial to start shortly thereafter and funding this p
Slide 134: © Silence Therapeutics 2019
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