Inclisiran ORION Program Update Dr David Kallend Previously

Inclisiran ORION Program Update Dr David Kallend Previously Chief Medical Officer The Medicines Company CRT, February 2020

Kallend, David MBBS (LON) Employment and Salary: The Medicines Company Stock options: The Medicines Company

Mechanism of action si. RNA 3

Inclisiran mechanism of action 3 x Gal. NAC modification enables specific and rapid hepatocyte uptake Inclisiran binds to ASGPR via 3 X Gal. NAC ASGPR is highly expressed on hepatocytes and recycles ~10 -15 minutes 1 ASGPR membrane Hepatocyte Clathrin-coated pit Hepatocyte cytoplasm ASGPR recycles Endocytosis Endosome Clathrin-coated vesicle s ratu ppa gi A Gol Inclisirin enters cytoplasm For incorporation into RISC complex Nucleus *ASGPR= asialoglycoprotein receptor, also known as the Ashwell−Morell lectin receptor, is expressed on hepatocytes and facilitates uptake and clearance of circulating glycoproteins with exposed terminal galactose and Gal. NAc glycans via clathrin-mediated endocytosis (Nair J et al. JACS 2014; 136: 16958 -16961. ). 1. Schwartz, A. L. , Fridovich, S. E. , and Lodish, H. F. J. Biol. Chem. 1982; 257: 4230– 4237 4

Inclisiran mechanism of action Inclisiran promotes m. RNA PCSK 9 cleavage by activating RISC c Hepato RISC sm topla yte cy 3 Hepato 2 Inclisiran is released from the endosome into the cytoplasm cyte m 4 ne Sense strand Inclisiran enters the RNAinduced silencing complex (RISC) Inclisiran embra 1 5 Antisense strand 7 8 The inclisiran antisense strand then directs RISC to messenger RNA (m. RNA). PCSK 9 m. RNA is cleaved 6 No synthesis of PCSK 9 proteins m. RNA s p gi A Gol atu par Nucleus 5

Phase II Foundations ORION-1 ORION-3 6

ORION-1: Efficacy 51% time-averaged LDL-C reduction over 6 -month dosing interval Starting Maintenance Mean percent change (± 95% CI) 56% p-value for all comparisons to placebo <0. 0001 6 -months time-averaged LDL-C reduction = 51% Days from first injection Source: Ray KK et al. NEJM 2017; 376: 1430 -40. 7

ORION-3: Long-term inclisiran efficacy Consistent long-term effect (>50%) of 300 mg inclisiran on LDL-C 8

Phase III Efficacy and Safety ORION-9 ORION-10 ORION-11 Confidential 9

ORION-9: Efficacy Durable and potent effect over 18 months • Percent and absolute change in LDL-C over time – observed values in ITT patients Time-averaged 45% 63 mg/d. L 50% 71 mg/d. L P-value for placebo – inclisiran comparison at each time point <0. 0001 1. All 95% confidence intervals are less than ± 2% and therefore are not visible outside data points; 2: time averaged observed data

ORION-9: Efficacy Legend and number of patients Placebo Inclisiran Change in LDL-C by genetic variants LDLR variants 131 125 Two variants 15 22 APOB 11 12 None identified 54 61 0 1 PCSK 9 gain of function Months from start of treatment 11

ORION-10: Efficacy Durable, potent and consistent effect over 18 months • Percent change in LDL-C over time – observed values in ITT patients Time-averaged 56% P-value for placebo – inclisiran comparison at each time point <0. 0001 1. All 95% confidence intervals are less than ± 2% and therefore are not visible outside data points; 2. time-averaged observed data 58%

ORION-11: Efficacy Durable, potent and consistent effect over 18 months • Percent change in LDL-C over time – observed values ITT patients <0. 0001 1. All 95% confidence intervals are less than ± 2% and therefore are not visible outside data points; 2. time-averaged observed data

ORION-11: Efficacy Potent, consistent response to inclisiran

Safety Summary • No difference from placebo for any laboratory parameter including hepatic, renal, hematology and muscle biomarkers • Adverse event profile generally similar to placebo • No imbalance in deaths or malignancy • Only adverse event considered to be related to administration of inclisiran are injection site reactions. These are predominantly mild and transient. • Overall highly reassuring safety profile in a high cardiovascular risk population Very high safety margin demonstrated in non-clinical studies

Conclusions and implications Inclisiran is the first cholesterol lowering si. RNA • Inclisiran achieves durable and potent LDL-C reduction with only 2 x yearly injection • Same dose and regimen for all patient populations e. g. renal and hepatic impairment, Ho. FH • Excellent safety profile in a high cardiovascular risk population • Administration by HCP potentially coincides with typical six-monthly patient visits – Lends itself to routine clinical practice – Enables health care provider control over medication adherence

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