ORION- 1 Impact of a 1- or 2-dose starting regimen of inclisiran, a novel siRNA inhibitor to PCSK9 on time averaged LDL-C reductions over 1 year Kausik K Ray, Ulf Landmesser, Lawrence A Leiter, David Kallend, Peter Wijngaard, R Scott Wright, and John JP Kastelein On behalf of the ORION-1 investigators

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Disclosure s Research grants: Amgen, Sanofi, Regeneron, MSD, Pfizer Consultancy: Amgen, Sanofi, Regeneron, MSD, Pfizer, Astra Zeneca, Lilly, Medicines Company, Kowa, IONIS, Takeda, Novo Nordisk, Boehringer Ingelheim, Esperion, Cipla, Algorithm, Abbvie, Resverlogix, Cerenis 3

Background LDL-C variability common, associated with worse outcomes Six month percent change in LDL-C among statin users from starting level1 Increase in death, CV outcomes with each 1 standard deviation of LDL-C variability2 60 23% 40 % change in LDL-C from BL 17% 16% 20 11% 10% -20 -40 Death Stroke Any coronary event Any CV event MI -60 1. Ray KK et al. N Engl J Med 2017; 376:1430-1440 2. Bangalore S et al. JACC 2015; 65: 1539-1548 4

Background PCSK9 inhibition reduces LDL-C and ASCVD1 PCSK9 monoclonal antibody treatment requires 12-26 injections per year1 Adherence unlikely to show substantial improvement over statins2 Limitations are most relevant in high risk patients needing lifelong therapy In the future can we do better? Sabatine MS et al. N Engl J Med 2017; 376:1713-1722 Hines D et al. ACC 2017 abstract #1203-313 5

Background RNAi is an intrinsic process for inhibiting mRNA Synthetic siRNA dicer dsRNA Cleavage Natural process of RNA interference Strand separation Targeted gene silencing RISC Complementary pairing mRNA Cleavage mRNA degradation 6

Background GalNAc-siRNA conjugates facilitate rapid hepatic uptake Asialoglycoprotein receptor (ASGPR) Highly expressed in hepatocytes only High rate of uptake GalNAc-siRNA inclisiran conjugate Clathrin-coated pit ASGPR (pH>5) GalNA c3 Recycling ASGPR Clathrin-coated vesicle Inclisiran siRNA conjugated to N-acetylgalactosamine Subcutaneous administration Targeted delivery to hepatocytes Hepatocyte cytoplasm Endosome 7

Methods ORION 1 trial design Screened (696) Stratified by country and Rx Randomized (501) One dose start Two dose start Placebo N=65 200 mg N=60 300 mg N=61* 500 mg N=65* Placebo N=62 100 mg N=61* 200 mg N=62* 300 mg N=61 Treated (497) Day 1 Day 14 Day 30 Study drug given 1st follow-up visit Monthly follow-up visits Day 1 Day 14 Day 30 Study drug given 1st follow-up visit Monthly follow-up visits Day 90 Day 90 Study drug given Day 180 Primary evaluation Day 180 Primary evaluation Day 210 End of study visit Day 210 End of study visit Completed (483) Day 360 Extended follow-up Day 360 Extended follow-up 8

Patients High-risk CV patients, balanced by randomization One dose starting regimen Two dose starting regimen Placebo N=65 Inclisiran N=186 N=62 N=184 Age Mean years 62 63 64 Male sex % 64.6 67.7 53.2 66.3 Prior ASCVD 69.2 67.9 74.2 68.3 Statin Rx % 70.3 74.4 77.0 70.2 LDL-C Mean mg/dL 128.5 125.9 125.2 133.0 Non-HDL-C 157.8 156.5 157.1 165.6 Apo-B 102.4 103.2 104.6 107.7 Lipoprotein(a) Median nmol/L 27.0 34.0 50.5 40.0 PCSK9 Mean ng/mL 404.7 428.7 431.3 416.2 9

Safety No safety concerns in study with follow up to Day 360 Similar overall adverse event profile and incidence for inclisiran and placebo No LFT elevations considered related to investigational drug Similar incidence of transient transaminase increases in randomized groups No difference in incidence of myalgias or CPK enzyme elevation One clinically relevant case of myonecrosis on placebo No deaths related to drug administration Two previously reported deaths1 >100 days, related to underlying disease 1: Patient A: History of CHD, MI and PCI died of a fatal MI on Day 104 of the study. (500mg x1 dose) Patient B: Developed complications of aortic aneurysm surgery including an aorto-esophageal fistula requiring esophagectomy, leading to infection of the prosthesis, sepsis, and stroke, culminating in death on Day 198 of the study. Patient also had AF, chronic renal failure, emphysema, HT and obesity. (200mg x2 doses) 10

Efficacy: One dose starting regimen Robust, sustained LDL-C reductions – 300 mg optimal 10 Mean percent change (±95% CI) Placebo -10 200mg P-value for all comparisons to placebo <0.0001 -20 300 mg -30 500 mg -40 -50 -60 30 60 90 120 150 180 210 240 Days from first injection 270 300 330 360 11

Efficacy: Two dose starting regimen Robust, sustained LDL-C reductions – optimal start regimen 300 mg x2 55.5% 52.5% 300 mg x2 31.4% 10 Mean percent change (±95% CI) Placebo 100 mg -10 P-value for all comparisons to placebo <0.0001 -20 200 mg -30 300 mg -40 -50 -60 30 60 90 120 150 180 210 240 Days from first injection 270 300 330 360 12

Sustained LDL-C lowering effects over time Time-averaged reduction from Day 1 to Day 360 One dose starting regimen Two dose starting regimen Tim e a d j u s t e d p e r c e n t c h a n g e i n L D L - C t o D a y 3 6 0 Inclisiran 200 mg Inclisiran 300 mg Inclisiran 500 mg Inclisiran 100 mg Inclisiran 200 mg Inclisiran 300 mg -30% -30% -37% -39% -40% -46% 13

Inclisiran dose 300mg sc Day 1, 90, 270 and 6- monthly Sustained >50% reduction in LDL-C for 6- months One dose starting regimen (300 mg) Two dose starting regimen (300 mg) % Change in LDL-C from Baseline 10 10 Time adjusted LDL-C for 6 months = 41% Time adjusted LDL-C for 6 months = 51% -10 -10 -20 -20 -30 -30 Q3 Q3 -40 -40 Mean Median Mean Median -50 -50 -60 -60 Q1 Q1 -70 -70 -80 -80 Day 90 Day 270 Day 90 Day 270 14

Efficacy: Day 360 LDL-C reduction in mg/dL Individual patient responses One dose starting regimen (N = 112) Two dose starting regimen (N = 142) 200 mg N = 30 300m g N = 38 500 mg N = 44 100 mg N = 41 200 mg N = 48 300 mg N = 53 40 40 -40 -40 -80 -80 -120 -120 -160 -160 -200 -200 15

Conclusions Robust LDL-C with 6 monthly inclisiran dosing Safety By day 360, patients are predictably returning towards baseline No safety signals at 1 year (>250 patient-years of observation) Dose and dose frequency 300 mg given s.c. at Day 1 and Day 90 represents the optimal starting dose 300 mg given s.c. at Day 270 then every 180 days is the maintenance dose This dosing schedule provides robust and consistent LDL-C lowering 46% time-averaged reduction over 12 months 51% time-averaged reduction over 6-monthly dosing interval Minimal within-patient variability in LDL-C reduction over time 16

Implications Inclisiran has moved into Phase III LDL-C lowering trials underway 3,000 subjects with ASCVD/ risk equivalents (ORION-10, -11) 400 subjects with HeFH (ORION-9) 60 subjects with HoFH (ORION-5) Parallel cardiovascular outcomes trial in preparation 15,000 subjects with high risk ASCVD (ORION-4) 17

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Safety No safety concerns in follow up to Day 360 Safety population One dose starting regimen Placebo Inclisiran Two dose starting regimen N=65 N=186 N=62 N=184 n (%) Any TEAE 51 (78.5) 155 (81.3) 51 (82.3) 153 (83.2) Serious 3 (4.6) 30 (16.1) 7 (11.3) 31 (16.8) Severe 2 (3.1) 18 (9.7) 22 (12.0) Related 12 (18.5) 39 (21.0) 19 (30.6) 52 (28.3) AE discontinuation 1 (1.6) (0.5) Injection site reaction (3.8) (6.5) TEAEs (treatment emergent adverse events) - similar incidence placebo vs inclisiran: One dose starting regimen: Nasopharyngitis, myalgia, back pain, cough, arthralgia, headache Two dose starting regimen: Myalgia, headache, diarrhea, nasopharyngitis, arthralgia, back pain 19