Frequency of Proteinuria in Trial 99* Supportive Slides 4/25/2017 6:07 AM Frequency of Proteinuria in Trial 99* Page 32 - Table 17

Mean total protein excretion Supportive Slides 15 4/25/2017 6:07 AM Effect of Back-titration in Patients With an Elevated Urinary Total Protein Excretion Rate 1200 Maximum 90th percentile 1000 800 75th percentile Mean total protein excretion rate, µg/min 600 Median 400 25th percentile 200 10th percentile Minimum 80 mg 40 mg Rosuvastatin dose 18 patients are included in this figure. Values below the limit of assay sensitivity are represented as zero.

Supportive Slides 32 4/25/2017 6:07 AM Resolution of Proteinuria With Rosuvastatin Dose Reduction First Back-titration Visit (n = 752) Rosuvastatin dose Dipstick protein 80 mg 40 mg None or trace, % 1+, % ≥ 2+, % 80.4 12.0 7.5 93.4 4.8 1.9 Briefing document May 7 renal section, T1 4MSU 21/46 (46%) patients had urine dipstick blood ≥ 1+ 20/21 (95%) no longer had combined proteinuria at first back-titration visit.

Supportive Slides 40 4/25/2017 6:07 AM Serum Calcium, Phosphorus, and Potassium in Patients With or Without Proteinuria: Rosuvastatin 80 mg Combined All Controlled/Uncontrolled and RTLD Pool Parameter N Baseline On-Treatment Calcium (mmol/L) No Proteinuria Proteinuria 437 145 2.3 (0.1) Phosphorus (mmol/L) 439 1.1 (0.2) Potassium (meq/L) 433 4.4 (0.4) Briefing document May 7 renal section, T1 4MSU Baseline and on-treatment values for patients with urine dipstick protein levels that remained “none or trace” or shifted to “++ or greater” during treatment .

Supportive Slides 32 4/25/2017 6:07 AM Frequency of Proteinuria by Visit Combined All Controlled and RTLD Pool Wk 4 Wk 6 Wk 8 Wk 12 Dose Urine protein none/ trace/+ at baseline, N Shift to ++ or greater, % Urine protein none/ trace/+ at baseline,N R5 mg 54 1.9 416 0.5 13 259 R10 mg 56 534 1.5 22 260 0.8 R20 mg 60 608 0.7 322 1.2 R40 mg 1659 1.7 389 1.0 1263 1 1205 1.8 R80 mg 55 7.3 95 8.4 PBO 69 315 1.6 28 159 1.3 A10 mg 14 271 297 117 0.9 A20 mg 313 299 2 A40 mg 38 0.0 A80 mg 11 49 S20 mg 294 115 S40 mg 316 S80 mg 305 0.3 285 P20 mg 128 127 P40 mg Briefing document May 7 renal section, T1 4MSU

Supportive Slides 15 4/25/2017 6:07 AM Effect of Back-titration of Rosuvastatin From 80 to 40 mg on Urinary Proteins Rosuva 80 mg N=63 Rosuva 40 mg Change Protein (nmol/mg Cr) IgG (157kD) 0.45 0.13 -0.32 Transferrin (90 kD) 0.44 0.11 -0.33 Albumin (69 kD) 0.72 0.29 -0.43 α-1 Microglobulin (31.8 kD) 1.57 0.31 -1.26 Retinol Binding Protein (21.2 kD) 5.19 0.47 -4.72 β-2 Microglobulin (11.8 kD) 0.58 0.27 -0.31 NAG activity (U/mg Cr) 0.03 0.02 -0.01

Supportive Slides 32 4/25/2017 6:07 AM Association of Antihypertensive Drug Use With Proteinuria in Hypertensive Patients Receiving Rosuvastatin 40 mg (n = 701) All Controlled/Uncontrolled Pool ARB ACEI CCB Diuretic Yes No N=116 N=585 N=287 N=414 N=194 N=507 N=197 N=504 % ≥ 2+ 1.7 2.1 1.9 2.0 1.0 2.4 % ≥ 1+ 14.7 12.1 10.5 9.9 12.9 9.1 10.7 Proteinuria - “none or trace” to “2+ or greater”.

Supportive Slides 2 4/25/2017 6:07 AM Urinary Protein Electrophoresis Patterns in Patients With Dipstick Positive Proteinuria Crestor ISSU Table 49 Patients, n Pattern Pretreatment ≥ 1+ (N = 13) On treatment† (N = 53) Normal 8 15 Tubular 22 Mixed 2 9 Glomerular 3 7 †Baseline none to 1+

Most Frequent Adverse Events All Controlled Pool Supportive Slides 9 4/25/2017 6:07 AM Most Frequent Adverse Events All Controlled Pool Patients, % Preferred term Placebo N = 382 Rosuva† N = 5721 Atorva N = 2940 Simva N = 1457 Prava N = 1278 Any AE, % 56.8 50.5 46.0 44.3 43.3 Pharyngitis 7.6 7.5 6.5 6.0 6.1 Pain 4.6 4.0 4.5 Headache 5.0 4.2 3.6 2.9 3.1 Myalgia 1.3 3.5 3.4 2.3 Asthenia 2.6 2.8 2.4 1.6 Back pain 1.8 Abdominal pain 4.7 2.7 2.0 Diarrhea 2.1 Flu syndrome 1.9 Nausea †Includes data for subjects who received rosuvastatin 80 mg.

Most Frequent Adverse Events by Dose Fixed-Dose Controlled Pool Supportive Slides 4/25/2017 6:07 AM Most Frequent Adverse Events by Dose Fixed-Dose Controlled Pool Patients, % Preferred term Rosuvastatin dose Placebo N = 365 5 mg N = 838 10 mg N = 1573 20 mg N = 749 40 mg N = 752 80 mg N = 264 Any adverse event 56.2 59.3 50.8 42.7 49.5 59.1 Pharyngitis 7.4 10.9 6.0 6.1 3.6 9.5 Headache 4.9 4.5 4.1 3.5 5.7 Pain 6.6 4.4 2.3 8.0 Myalgia 1.4 3.9 3.3 1.6 7.2 Diarrhea 3.0 3.2 1.5 Abdominal pain 3.1 2.7 1.7 3.4 Nausea 2.6 2.9 Asthenia 2.4 2.5 Constipation 1.2 4.2 Back pain 2.2 2.8 1.9

Number of F/U urinalysis visits Median number of F/U visits Supportive Slides 40 4/25/2017 6:07 AM Duration of Treatment and Number of Urinalysis Visits per Dose Combined All Controlled and RTLD Pool Treatment Dose N Mean (SD) days on dose PYR Number of F/U urinalysis visits Median number of F/U visits Placebo 368 62.6 (21.8) 63 831 2 Rosuvastatin 5 mg 10 mg 20 mg 40 mg 80 mg 639 1189 1437 2496 798 148.6 (131.1) 115.2 (111.9) 67.5 (40.2) 105.8 (78.3) 45.5 (13.5) 260 365 262 719 99 1294 1910 2002 6952 976 1 3 Atorvastatin 696 659 241 105.6 (95.5) 69.2 (42.2) 49.2 (26.3) 46.0 (16.4) 201 125 32 46 1051 805 247 400 Simvastatin 505 352 334 118.3 (95.0) 92.7 (46.5) 51.2 (35.3) 163 89 47 809 508 934 Pravastatin 20 mg 40 mg 187 67 144.6 (112.5) 232.4 (64.3) 74 43 349 117

Supportive Slides 4/25/2017 6:07 AM HDL-C: % Change From Baseline Rosuvastatin : Baseline HDL-C < 40 mg/dL or ≥ 40 mg/dL Trial 65 – STELLAR (Wk 6) < 40 mg/dL ≥ 40 mg/dL N 21 27 27 135 133 130 Data presented as LS mean.

Supportive Slides 4/25/2017 6:07 AM Icterus Case 1 (310/01237) 68 year-old Caucasian male, who after 17 weeks of rosuvastatin 10 mg treatment noted icterus and brown urine ALT and AST values in this subject increased to 223 U/L (3.4 x ULN) and 91 (2.5 x ULN) with a mildly elevated bilirubin of 2.1 mg/dL (2.1 x ULN) Patient was hospitalized; rosuvastatin, metformin, captopril, nilvadipine, clopidogrel were all withdrawn Liver histology showed normal parenchyma. He was discharged. Follow-up liver function 1 week after the event showed resolution.

Supportive Slides 4/25/2017 6:07 AM Icterus Case 2 (2265/09060) 73 year-old Caucasian male subject, who after 11 weeks of rosuvastatin 10 mg treatment reported icterus. ALT and AST values in this subject reached 914 (38.1 x ULN) and 699 (38.3 x U/L), respectively, with a bilirubin of 11.8 mg/dL (10.7 x ULN). Hepatitis titers: HepBs Ag negative, positive IgM Anti-HepBc and HepA IgG antibodies Follow up liver function tests showed resolution

Protein Handling by the Kidney Supportive Slides 4/25/2017 6:07 AM Protein Handling by the Kidney Glomerular proteinuria Tubular proteinuria Normal Plasma concentration, mg/L 40,000 4 40,000 4 40,000 4 2 2 2000 2 2 2 Filtered load, mg/day if GFR – 150L/day 360 360 360,000 360 360 360 % reabsorbed 95 95 95 95 50 50 Daily excretion, mg 18 18 18,000 18 180 180 Albumin Low molecular weight proteins

N with creatinine increase Supportive Slides 31 4/25/2017 6:07 AM Creatinine Changes in Patients With Proteinuria at Last Visit, ≥ 96 Wk of Rosuvastatin Treatment Combined All Controlled/Uncontrolled and RTLD Pool C 9.4.5.4.5.2, C9.9.4.5.4.5 Rosuva dose N with N/Tr at baseline N (%) with proteinuria N with creatinine increase > 30 % > 0.5 mg/dL > 1.0 mg/dL 5 mg 239 10 mg 821 4 (0.5) 20 mg 111 1 (0.9) 40 mg 99 2 (2.0) 80 mg 589 37 (6.3) 2 ≥ 40 mg† 796 8 (1.0) †Includes patients who back-titrated from the 80-mg dose. No patients with creatinine > 1 mg/dL.

Post Launch Safety Assessment Ongoing Clinical Trials Program Supportive Slides 4/25/2017 6:07 AM Post Launch Safety Assessment Ongoing Clinical Trials Program Atherosclerosis regression METEOR – 840 patients; placebo-controlled 40 mg ASTEROID – 400 patients, 40 mg rosuvastatin Outcomes studies GISSI-HF – 5250 patients with CHF, placebo-controlled 10 mg rosuvastatin CORONA – 4800 patients with CHF, placebo-controlled 10 mg rosuvastatin AURORA - 2700 patients with CRF on dialysis, placebo-controlled 10 mg rosuvastatin JUPITER – 15,000 subjects with elevated CRP, placebo-controlled 20 mg rosuvastatin

Supportive Slides 37 4/25/2017 6:07 AM Cumulative Risk of Myopathy Patients Receiving ≥ 40 mg of Rosuvastatin Combined All Controlled/Uncontrolled and RTLD Pool

Benefit/Risk of High-Dose Statin Therapy Supportive Slides 4/25/2017 6:07 AM Benefit/Risk of High-Dose Statin Therapy Rosuva 20 / 40 Atorva 40 / 80 Simva 40 / 80 % LDL-C ↓ 55 / 63 50 / 60 41 / 47 ALT > 3 x ULN 0.1 / 0.3 0.6 / 2.3 0.9 / 2.1 CK > 10 x ULN 0.2 / 0.4 0.5 / 0.9 0.1 / 1.2 Proteinuria 0.7 / 1.2 0 / 0.3 0.3 / 0

Familial Hypercholesterolemia (FH) Supportive Slides 4/25/2017 6:07 AM Familial Hypercholesterolemia (FH) FH is common There are 500,000 patients in the US (frequency 1 person in 500) FH causes early CHD Average age of CHD onset is 45 - 50 years in men, 55 - 60 years in women FH is difficult to treat Most FH patients cannot be adequately treated to NCEP LDL-C goal

Familial Hypercholesterolemia (FH): Cumulative Probability of CAD Supportive Slides 4/25/2017 6:07 AM Familial Hypercholesterolemia (FH): Cumulative Probability of CAD 1.0 Non-FH Women 0.9 Non-FH Men 0.8 FH Women 0.7 FH Men 0.6 Cumulative probability of clinical CAD 0.5 0.4 0.3 0.2 0.1 0.0 90+ 25-30 30-35 35-40 40-45 45-50 50-55 55-60 60-65 65-70 70-75 75-80 80-85 85-90 Age MED PED Registry 2001.

Supportive Slides 4/25/2017 6:07 AM LDL-C: % Change From Baseline Rosuvastatin vs Atorvastatin: Heterozygous FH Trial 30 (Wk 6 - 18) 20 mg 40 mg 80 mg * * * *P < .05 vs atorvastatin; data presented as LS means ± SE.

Additional LDL-C Reduction Rosuvastatin 40 mg vs 20 mg Study 30 Supportive Slides 4/25/2017 6:07 AM Additional LDL-C Reduction Rosuvastatin 40 mg vs 20 mg Study 30 Baseline LDL-C 290 mg/dL 20 mg: reduction 47% Mean LDL-C = 154 mg/dL 40 mg: reduction 54% Mean LDL-C = 133 mg/dL Additional LDL-C reduction with 40 mg = 21 mg/dL or 13.6% further decrease over 20 mg

Supportive Slides 4/25/2017 6:07 AM LDL-C: % of High-Risk FH Patients Achieving NCEP ATP III LDL-C Goal Trial 30 * *P < .05

Stein, et al. J Am Col Cardiol 2003. Supportive Slides 4/25/2017 6:07 AM % of High-Risk FH Patients Achieving NCEP ATP III LDL-C Goal in 2 Different Studies Rosuvastatin 40 mg Atorvastatin 40 mg + Ezetimibe 10 mg Atorvastatin 80 mg Atorvastatin 80 mg Note: no statistical analyses were performed. LDL-C: < 100 mg/dL (2.59 mmol/L). Stein, et al. J Am Col Cardiol 2003.

Mortality log odds ratio % in cholesterol reduction Supportive Slides 29 4/25/2017 6:07 AM Benefits of Cholesterol Lowering Meta-analysis of 38 Primary and Secondary Intervention Trials –0.0 –0.2 –0.4 Mortality log odds ratio –0.6 Total mortality (P = .004) –0.8 CHD mortality (P = .012) –1.0 4 8 12 16 20 24 28 32 36 40 44 48 52 % in cholesterol reduction Gould AL, et al. Circulation. 1998;97:94-952.

LDL-C 1% decrease reduces CHD risk by 1% Supportive Slides 4/25/2017 6:07 AM Relationship Between Changes in LDL-C Levels and CHD Risk: NCEP ATP III LDL-C 1% decrease reduces CHD risk by 1% Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670. 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

HDL-C 1% increase reduces CHD risk by 3% Supportive Slides 4/25/2017 6:07 AM Relationship Between Changes in HDL-C Levels and CHD Risk: NCEP ATP III HDL-C 1% increase reduces CHD risk by 3% Third Report of the NCEP Expert Panel. NIH Publication No. 01-3670. 2001. http://hin.nhlbi.nih.gov/ncep_slds/menu.htm

Supportive Slides 4/25/2017 6:07 AM Achievement of NCEP ATP-II LDL-C Goals at Wk 52 (Titrated to Goal as Needed) Rosuvastatin 10 - 40 mg compared With Atorvastatin 10 - 80 mg Trial 26 Reached on 80 mg Reached on 40 mg Reached on 20 mg * 96% 87% 100 90 80 Reached on 10 mg 70 60 Patients, % 50 82% 40 59% 30 20 10 RSV ATV *P < .05.

Supportive Slides 4/25/2017 6:07 AM Effect of Rosuvastatin on Plasma Concentrations of Ethinyl Estradiol and Norgestrel Compound OCS OCS + rosuvastatin Treatment effect 90% CI Ethinyl estradiol Cmax (pg/mL) 159 198 1.25 1.17, 1 .33 Norgestrel Cmax (ng/mL) 3.46 4.27 1.23 1.14, 1.33 Ethinyl estradiol AUC(0-24)(pg·h/mL) 1340 1690 1.26 1.19, 1.34 Norgestrel AUC(0-24)(ng·h/mL) 62.0 82.8 1.34 1.25, 1.43

22 Supportive Slides 4/25/2017 6:07 AM LDL-C: % Change From Baseline Rosuvastatin: Homozygous FH < 18 Yr Trial 54 (Wk 6 - 12) RSV 20 mg RSV 40 mg N = 8 (7 included in analysis). Four patients had defective receptor status; others were unknown. Range at Wk 12: (–47.5 to –12.5).

Supportive Slides 4/25/2017 6:07 AM TG: % Change From Baseline Rosuvastatin vs Placebo: Type IIB and IV Trial 35 (Wk 6) n = 7 19 10 15 11 12 10 17 10 15 Baseline TG Type IIB = 416 and Type IV = 500. Data presented as LS means.