SPIRE Program: Studies of PCSK9 Inhibition and the Reduction of Vascular Events Unanticipated attenuation of LDL-c lowering response to humanized PCSK9 antibody over time Ridker PM, Tardif J-C, Amarenco P, et al. Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab. NEJM 2017; 376:1517-1526 Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. NEJM 2017; 376:1527-1539

SPIRE: Background and Objective In six multinational trials evaluating bococizumab, a PCSK9 inhibitor, the initially achieved LDL-c lowering was significantly attenuated over time due to antidrug antibodies, and the relative reduction in cholesterol levels varied widely also in patients without antidrug antibody development. Study Objective The SPIRE-1 and SPIRE-2 studies were designed to assess the clinical efficacy and safety of bococizumab versus placebo in patients at high CV risk with 2 different baseline levels of LDL-c. When the results of the six SPIRE lipid-lowering trials became available, the sponsor discontinued prematurely the ongoing SPIRE-1 and SPIRE-2 outcome trials. PCSK9: proprotein convertase subtilisin–kexin type 9; LDL-c: low density lipoprotein cholesterol; CV: cardiovascular Ridker PM, et al., N Engl J Med 2017; 376:1517-1526 Ridker PM, et al., N Engl J Med 2017; 376:1527-1539

SPIRE lipid-lowering studies Attenuation of LDL-c response over time, due to the development of antidrug antibodies in 4,449 patients included in 6 studies LDL-c: low density lipoprotein cholesterol; Ridker PM, et al., N Engl J Med 2017; 376:1517-1526

SPIRE-1 & -2: Inclusion criteria Inclusion criteria in both studies Secondary prevention cohort: history of CV event, or IS, or coronary artery or peripheral artery revascularization High-risk primary prevention cohort: history of DM, or KD, or PVD plus at least 1 CV risk factor* or history of FHC Lipid levels inclusion criteria SPIRE-1: LDL-c ≥70 mg/dL (1.81 mmol/L) or non-HDL-c ≥100 mg/dL (2.59 mmol/L) SPIRE-2: LDL-c ≥100 mg/dL (2.59 mmol/L) or non-HDL-c ≥130 mg/dL (3.36 mmol/L) (*) smoking history, HDL-c <40 mg/dL (<1.0 mmol/L), hs-CRP >2.0 mg/L; Lp(a) > 50 mg/dL, microalbuminuria, asymptomatic coronary stenosis; age ≥50 years for men and ≥60 years for women CV: cardiovascular; IS: ischemic stroke; DM; diabetes mellitus; KD: kidney disease; PVD: peripheral vascular disease; FHC: familial hypercholesterolemia; LDL-c: low density lipoprotein cholesterol; HDL-c: high density lipoprotein cholesterol; hs-CRP: high sensitivity C-reactive protein; Lp(a): lipoprotein(a); Ridker PM, et al., N Engl J Med 2017; 376:1527-1539

SPIRE-1 & -2: Study design Patients at high CV risk on statins* for at least 4 weeks (N=27,438) Bococizumab 150 mg SC every 2 weeks Placebo Median follow-up: 10 months Primary endpoint: composite of non-fatal MI, non-fatal stroke, hospitalization for UA requiring urgent revascularization, or CV death (*) atorvastatin ≥40 mg daily, rosuvastatin ≥20 mg daily, or simvastatin ≥40 mg daily - statin therapy was continued throughout the studies CV: cardiovascular; SC: subcutaneously; MI: myocardial infarction, UA: unstable angina; Ridker PM, et al., N Engl J Med 2017; 376:1527-1539

SPIRE-1 & -2: Primary endpoint HR 0.99 0.79 0.88 95%CI 0.80-1.22 0.65-0.97 0.76-1.02 P value 0.94 0.02 0.08 HR: hazard ratio; CI: confidence interval; Ridker PM, et al., N Engl J Med 2017; 376:1527-1539

SPIRE-1 & -2: Lipid lowering results Mean percent change from baseline in both studies combined LDL-c: low density lipoprotein cholesterol; HDL-c: high density lipoprotein cholesterol; Ridker PM, et al., N Engl J Med 2017; 376:1527-1539

SPIRE-1 & -2: Pre-specified stratified analyses LDL-c: low density lipoprotein cholesterol; Ridker PM, et al., N Engl J Med 2017; 376:1527-1539

SPIRE-1 & -2: Pre-specified stratified analyses Primary outcome stratified by randomization date event rate per 100 patient-years P=0.03 P=0.83 Ridker PM, et al., N Engl J Med 2017; 376:1527-1539

SPIRE: Conclusions PCSK9 inhibition with bococizumab reduces LDL-c by 55-60% when given as an adjunct to statin therapy, but this effect significantly attenuates over time due to the development of anti-drug antibodies. Despite anti-drug antibody production and the early trial termination, bococizumab significantly reduced cardiovascular event rates in the higher-risk SPIRE-2 trial of those with LDL-c >100 mg/dL, but not in the lower-risk SPIRE-1 trial of those with LDL-c >70 mg/dL. Clinical benefits were greater and statistically significant in analyses of those who achieved and sustained greater absolute and relative LDL-c reductions, and in those who were exposed to therapy for a longer time, a finding that supports the hypothesis that ‘lower is better for longer’. Ridker PM, et al., N Engl J Med 2017; 376:1527-1539