Silence Therapeutics PLC · NASDAQ:SLN

Silence Therapeutics — European Hematology Association (EHA) Congress 2018

13 slides from Silence Therapeutics's conference presentation, Jun 14, 2018

1. Slide 1: Development of a GalNAc siRNA conjugate targeting TMPRSS6 for iron overload disorders

   EHA June 14th to 17th 2018; Iron: from basic science to clinical application Development of a GalNAc siRNA conjugate targeting TMPRSS6 for the treatment of iron overload disorders such as b-Thalassaemia Ute Schaeper, PhD Project Leader Drug Discovery

2. Slide 2: Our internal pipeline

   Our internal pipeline © Silence Therapeutics 2018 2

3. Slide 3: Iron overload disorders

   Iron overload disorders Organs affected by iron overload Diseases with iron overload > β-Thalassaemia > Myelodysplastic Syndrome > Hereditary Haemochromatosis > Aplastic Anaemia > Sideroblastic Anaemia If untreated, iron accumulation in organs leads to severe damage, e.g. heart, liver & endocrine or

4. Slide 4: Rationale for targeting TMPRSS6 in iron overload disorders

   Rationale for targeting TMPRSS6 in iron overload disorders > TMPRSS6 is a negative regulator of the BMP/SMAD HJV BMPR Macrophages signaling pathway; activation of the pathway induces BMP hepcidin expression > Hepcidin reduces uptake of dietary iron and the Ferroportin release of iron from storage ce

5. Slide 5: Therapeutic activity of SLN124 in a disease model of Hereditary Haemochromatosis type 1 (1/2)

   Therapeutic activity of SLN124 in a disease model of Hereditary Haemochromatosis type 1 (1/2) Study design Collaboration with d1 wk 3 Hfe-/- mice Prof. Dr. Martina Muckenthaler model of HH type 1 1X sc, HFE-/- mice, females, 6 wks, n=6-7 Heidelberg University, Germany TMPRSS6 mRNA Hepcidin (Serum) T

6. Slide 6: Therapeutic activity of SLN124 in a disease model of Hereditary Haemochromatosis type 1 (2/2)

   Therapeutic activity of SLN124 in a disease model of Hereditary Haemochromatosis type 1 (2/2) Study design Collaboration with d1 wk 3 Hfe-/- mice Prof. Dr. Martina Muckenthaler model of HH type 1 1X sc, HFE-/- mice, females, 6 wks, n=6-7 Heidelberg University, Germany Kidney Iron Spleen Iron Spleen

7. Slide 7: SLN124 improves anaemia and normalises spleen size in a murine model of b-thalassaemia intermedia

   SLN124 improves anaemia and normalises spleen size in a murine model of b-thalassaemia intermedia Study design Hbbth3/+ mice Collaboration with d1 wk 2 wk 5 model of b-thalassaemia Dr. J. Vadolas & Dr. G. Grigoriadis sc,Hbbth3/+ & wt mice, n=5-8 intermedia Monash Medical Centre/Melbourne, Australia

8. Slide 8: SLN124 reduces ROS in red blood cells of b-thalassaemia intermedia mice

   SLN124 reduces ROS in red blood cells of b-thalassaemia intermedia mice Study design Hbbth3/+ mice Collaboration with d1 wk 2 wk 5 model of b-thalassaemia Dr. J. Vadolas & Dr. G. Grigoriadis sc,Hbbth3/+ & wt mice, n=3-6 intermedia Monash Medical Centre/Melbourne, Australia Reactive Oxygen Species Re

9. Slide 9: SLN124 ameliorates RDW and normalises proportion of reticulocytes in b-thalassaemia intermedia model

   SLN124 ameliorates RDW and normalises proportion of reticulocytes in b-thalassaemia intermedia model Study design Hbbth3/+ mice Collaboration with d1 wk 2 wk 5 model of b-thalassaemia Dr. J. Vadolas & Dr. G. Grigoriadis sc, Hbbth3/+ & wt mice. n=5-8 intermedia Monash Medical Centre/Melbourne, Austra

10. Slide 10: SLN124 ameliorates RBC maturation in bone marrow

    SLN124 ameliorates RBC maturation in bone marrow th3/+ th3/+ th3/+ wt 1 2 3 4 5 CD44 2 1 2 1 4 3 4 3 Pro- Basoph. Polychr. Orthochr. Retic. Erythr. 5 PBS CTRL SLN124 5 erythrobl. normobl. normobl. normobl. FSC 60 Bone Marrow E ry th ro id s u b p o p u la tio n s 40 % c e lls 1 : p ro e r y th r o b

11. Slide 11: SLN124 reduces ineffective erythropoiesis in spleen

    SLN124 reduces ineffective erythropoiesis in spleen th3/+ th3/+ th3/+ wt 1 2 3 4 5 1 CD44 2 22 11 4 3 4433 Pro- Basoph. Polychr. Orthochr. Retic. Erythr. 5 PBS CTRL SLN124 55 erythrobl. normobl. normobl. normobl. FSC 100 Spleen 80 E ry th ro id s u b p o p u la tio n s 1 : p ro e r y th r o b la s t

12. Slide 12: SLN124 - Summary

    SLN124 - Summary > Highly potent, specific, safe and long-acting GalNAc-siRNA conjugate > Efficacious in lowering systemic iron levels and improving erythropoiesis and RBC parameters in murine disease models > Demonstrated therapeutic efficacy in clinically relevant animal models for b-thalassaemia

13. Slide 13: Acknowledgements

    Acknowledgements S. Dames Dr. K. Löffler Heidelberg University Monash Medical Centre/Melbourne M. Eisermann Prof. Dr. M. Muckenthaler Dr. J. Vadolas Dr. S. Schubert Dr. S. Altamura Dr. G. Grigoriadis Dr. C. Frauendorf Dr. L. Bethge N. Roeder M. Aleku Dr. U. Zügel © Silence Therapeutics 2018 13

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