LAPLACE-TIMI 57 Primary Results y A Double-blind, Randomized, - PowerPoint PPT Presentation

LAPLACE-TIMI 57 Primary Results y A Double-blind, Randomized, Placebo-controlled, Dose-ranging Study to Evaluate the Efficacy, Safety, and Tolerability of a Monoclonal Antibody to PCSK9 in Combination with a Statin in Patients with Hypercholesterolemia R b Robert P. Giugliano, MD, SM, FAHA, FACC t P Gi li MD SM FAHA FACC TIMI Study Group, Cardiovascular Division Brigham and Women’s Hospital g p Harvard Medical School, Boston, MA S Supported by research grant from Amgen, Inc. t d b h t f A I An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

PCSK9 Regulates the Surface Expression of LDLRs by Targeting LDLRs for Lysosomal Degradation LDL receptor AMG 145, a fully human monoclonal antibody that binds PCSK9, was well tolerated and lowered LDL in phase Ia and Ib studies (Dias CS, JACC published online Oct 17, 2012. http://dx.doi.org/10.1016/j.jacc.2012.08.986) (Dias CS, JACC published online Oct 17, 2012. http://dx.doi.org/10.1016/j.jacc.2012.08.986) Brown MS, et al. Proc Natl Acad Sci U S A . 1979;76:3330-3337. Qian YW, et al. J Lipid Res . 2007;48:1488-1498. Steinberg D, et al. Proc Natl Acad Sci U S A . 2009;106:9546-9547. Horton JD, et al. J Lipid Res . 2009;50:S172-S177. Goldstein JL, et al. Arterioscler Thromb Vasc Biol . 2009;29:431-438. Zhang DW, et al. J Biol Chem. 2007;282:18602-18612.

Objectives Objectives: To compare 12 weeks of AMG 145 ( i (given SC Q2 or Q4 weeks) vs placebo in SC Q2 Q4 k ) l b i stable patients with hypercholesterolemia on a statin ± ezetimibe: a statin ± ezetimibe: – Primary: % change in LDL-C* – Secondary: changes in other lipoproteins pharmacokinetics/pharmacodynamics tolerability and safety * measured using ultracentrifugation in a central core laboratory An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Study Design 78 centers Placebo SC Q2W 5 countries 78 Subjects 70 mg AMG 145 SC Q2W g Screening and 79 Subjects Placebo Run-in 105 mg AMG 145 SC Q2W Period 79 Subjects 140 mg AMG 145 SC Q2W 78 S bj 78 Subjects t S b Subcutaneous t injection of 6 mL placebo Placebo SC Q4W 77 Subjects Fasting LDL-C 280 mg AMG 145 SC Q4W 280 mg AMG 145 SC Q4W 5-10 days 5-10 days before 79 Subjects randomization 350 mg AMG 145 SC Q4W 79 Subjects 420 mg AMG 145 SC Q4W Maximum 6 weeks Maximum 6 weeks 80 Subjects S Visits: Day 1 Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Week 14 Q2W: Primary Endpoint p Q4W: Q4W: Assessed 934 screened 631 random. 629 treated ( *2 subjects assigned placebo Q4W received no study drug) An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Kohli P, et al. Clin Cardiol . 2012;35:385 ‐ 391.

Major Entry Criteria • Age 18–80 years • Stable dose of statin ± ezetimibe for 4 wks St bl d f t ti ± ti ib f 4 k • Fasting LDL-C ≥ 85 mg/dL • Fasting triglycerides ≤ 400 mg/dL Fasting triglycerides ≤ 400 mg/dL • No other prescription lipid lowering therapy • No recent ACS revascularization stroke • No recent ACS, revascularization, stroke • No major comorbidities Randomization stratified by: 1) Baseline LDL (<130 vs ≥ 130 mg/dL) 2) Use of ezetimibe at baseline An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School Kohli P, et al. Clin Cardiol . 2012;35:385 ‐ 391.

Baseline Characteristics Placebo AMG 145 Characteristic (N=157) (N=474) Age, years, mean (SD) 60 (9) 61 (10) Sex, female, % 54% 50% 94% 94% 87% 87% Race white Race, white, % % P = NS LDL, mg/dL, mean (SD) 124 (29) 123 (27) for all LDL < 130 mg/dL, % 66% 65% co comparisons pa so s Ezetimibe, % 10% 9% Intensive statin regimen*, % 25% 31% Diabetes mellitus, % 11% 18% Body mass index (kg/M 2 ), mean (SD) 30 (5) 30 (6) Coronary artery disease, % 27% 31% Free PCSK9 (ng/mL) mean (SD) Free PCSK9 (ng/mL), mean (SD) 450 (124) 450 (124) 443 (126) 443 (126) *rosuvastatin ≥ 20 mg, atorvastatin ≥ 40 mg, simvastatin 80 mg or ezetimibe + any statin An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Primary Endpoint: AMG 145 Reduced LDL-C at 12 wks AMG 145 Reduced LDL-C at 12 wks AMG 145 Q2W AMG 145 Q4W 70 mg 105 mg 140 mg 280 mg 350 mg 420 mg N = 79 N = 79 N = 79 N = 79 N = 78 N = 78 N = 79 N = 79 N = 79 N = 79 N = 80 N = 80 0 t Week 12 -10 * p < 0 0001 for each dose vs placebo p < 0.0001 for each dose vs placebo -20 20 Placebo (SE) a -30 -40 40 ge LDL-C vs P -41.8 -41.8 -50 -50.0 -50.3 -60 % Chang -60.2 -70 -66.1 -80 LDL-C at 12 wks LDL C at 12 wks Mean (mg/dL) 73 53 44 69 60 58 (SD) (25) (21) (25) (28) (23) (26) An Academic Research Organization of NOTE: LDL-C measured using ultracentrifugation in a central core laboratory Brigham and Women’s Hospital and Harvard Medical School

% Reduction in LDL with Top 2 AMG 145 Doses: Major Subgroups AMG 145 Doses: Major Subgroups 140 mg Q2W dose of AMG 145 420 mg Q4W dose of AMG 145 reduced LDL at 12 weeks ranging reduced LDL at 12 weeks ranging Baseline from 56-74% in key subgroups y g p from 38-57% in key subgroups y g p Characteristics All patients -66% (-71, -61) -50% (-56, -45) * UC = Ultra centrifugation An Academic Research Organization of * P interaction = 0.048, all others >0.05 Brigham and Women’s Hospital and Harvard Medical School

AMG 145 Q2W Dose Response: % Change in LDL C Through 12 Wks % Change in LDL-C Through 12 Wks 10 in 0 0 m Baseline i –10 p < 0.0001 for weeks 2-12 for each dose vs placebo DL-C –20 –30 –30 alculated LD Change from –40 –50 –60 Ca Mean % C –70 number of patients –80 78 74 77 78 76 77 74 79 78 77 75 76 76 76 –90 79 76 76 77 73 77 74 78 78 77 77 76 76 77 77 75 75 76 76 73 73 –100 Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Study Drug Administration Placebo Q2W (n = 78) Placebo Q2W (n = 78) AMG145 70 mg Q2W (n = 79) AMG145 70 mg Q2W (n = 79) AMG145 105 mg Q2W (n = 79) AMG145 140 mg Q2W (n = 78) An Academic Research Organization of LDL-C calculated using the Friedewald equation Brigham and Women’s Hospital and Harvard Medical School

AMG 145 Q4W Dose Response: % Change in LDL C Through 12 Wks % Change in LDL-C Through 12 Wks 10 in 0 0 m Baseline i –10 p < 0.0001 for weeks 2-12 for each dose vs placebo DL-C –20 –30 –30 alculated LD Change from –40 –50 –60 Ca Mean % C –70 number of –80 patients 77 71 77 76 75 75 76 –90 79 75 77 74 77 74 78 79 9 70 0 78 8 72 76 6 74 77 80 69 78 76 74 76 77 –100 Baseline Week 2 Week 4 Week 6 Week 8 Week 10 Week 12 Study Drug Study Week Administration Placebo Q4W (n = 77) AMG145 280 mg Q4W (n = 79) AMG145 350 mg Q4W (n = 79) AMG145 420 mg Q4W (n = 80) An Academic Research Organization of LDL-C calculated using the Friedewald equation Brigham and Women’s Hospital and Harvard Medical School

AMG 145 Dose Response: % Change in LDL-C Wks 8-12 (placebo adjusted) % Change in LDL C Wks 8 12 (placebo adjusted) 0 Week 8 Week 9 Week 10 Week 11 Week 12 –10 Calculated –20 ean (SE) –30 Change in C Placebo, Me –40 –50 –60 –60 ercentage C LDL-C vs. P –70 –80 Pe L –90 Study Drug Study Drug Administration Administration –100 n = 22 n = 7 n = 23 n = 16 n = 22 280 mg 70 mg n = 25 n = 6 n = 25 n = 16 n = 26 n = 25 n = 25 n = 11 n = 11 n = 28 n = 28 n = 15 n = 15 n = 28 n = 28 350 mg 350 mg 105 mg 105 mg n = 27 n = 27 n = 10 n = 10 n = 26 n = 26 n = 18 n = 18 n = 27 n = 27 140 mg n = 29 n = 16 n = 30 n = 20 n = 27 420 mg n = 27 n = 17 n = 26 n = 19 n = 28 An Academic Research Organization of LDL-C calculated using the Friedewald equation Brigham and Women’s Hospital and Harvard Medical School

Secondary Results at 12 Wks with Top 2 AMG 145 Doses with Top 2 AMG 145 Doses -33% 33% -32% -43% -44% -48% -61% -36% -42% -43% -48% -53% -56% P < 0.0001 versus placebo for all parameters Q2W, every 2 weeks; Q4W, every 4 weeks; SE, standard error An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School

Safety Q2W Dose Groups Q4W Dose Groups Adverse Events, AMG 145 AMG 145 Patient Incidence, Placebo Placebo 70 mg g 105 mg g 140 mg g 280 mg g 350 mg g 420 mg g Total n N=78 N=79 N=79 N=78 N=77 N=79 N=79 N=80 N=629 Adverse events 33 41 52 43 38 45 48 48 348 Serious AE 4 0 1 4 0 2 2 2 15 Lead to drug DC 0 0 0 2* 0 0 0 0 2 50 ↑ Drug related AEs 7 4 9 4 4 6 7 9 L Lead to drug DC d t d DC 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Injection site rxn 2 1 1 0 1 2 3 1 11 AST or ALT >3x ULN 1 0 0 0 0 0 0 0 1 CPK >5X ULN 0 1 1 1 0 0 0 1 4** CV events‡ 1 1 0 4 0 1 1 0 8 Death 0 0 0 1 0 0 0 0 1 *Both events were reported as non-serious by the investigators. †All 50 were reported as non-serious by the investigator and none led to discontinuation of drug ** All were asymptomatic ‡Acute coronary syndrome, coronary revascularization, TIA, congestive heart failure requiring hospitalization, or death An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School