Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab

Ridker, Paul M.; Tardif, Jean‐Claude; Amarenco, Pierre; Duggan, William; Glynn, Robert J.; Jukema, J. Wouter; Kastelein, John J.P.; Kim, Albert M.; Köenig, Wolfgang; Nissen, Steven E.; Revkin, James H.; Rose, Lynda M.; Santos, Raul D.; Schwartz, Pamela F.; Shear, Charles L.; Yunis, Carla

doi:10.1056/nejmoa1614062

Cited by 295 publications

(237 citation statements)

References 14 publications

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“…This observation within a single subject in our study is especially interesting given that the pooled analysis of 6 SPIRE lipid-lowering trials reported ADA titer-dependent reductions in bococizumab's LDL-C-lowering efficacy after the Week 12 timepoint. 12 Overall, bococizumab was well tolerated in both study populations in our study and our data suggested no previously unknown risks from the use of this agent in these subjects. However, on November 1, 2016, Pfizer Inc. announced the discontinuation of the global clinical development program for bococizumab.…”

Section: Discussionsupporting

confidence: 69%

Efficacy and Safety of Bococizumab (RN316/PF-04950615), a Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, in Hypercholesterolemic Japanese Subjects Receiving a Stable Dose of Atorvastatin or Treatment-Naive　― Results From a Randomized, Placebo-Controlled, Dose-Ranging Study ―

Yokote

Kanada²,

Matsuoka³

et al. 2017

Circ J

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Section: Discussionsupporting

confidence: 69%

Efficacy and Safety of Bococizumab (RN316/PF-04950615), a Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9, in Hypercholesterolemic Japanese Subjects Receiving a Stable Dose of Atorvastatin or Treatment-Naive　― Results From a Randomized, Placebo-Controlled, Dose-Ranging Study ―

Yokote

Kanada²,

Matsuoka³

et al. 2017

Circ J

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“…Direct evidence for the benefit of even greater reductions in LDL-C among patients with LDL-C ≥190 mg/dL in primary prevention may be inferred indirectly from the recently reported SPIRE-2 trial (Studies of PCSK9 Inhibition and the Reduction of Vascular Events), [27][28][29] evaluating the efficacy of PCSK9 inhibition with bococizumab in reducing the risk of major cardiovascular events in subjects with LDL-C ≥100 mg/dL despite maximally tolerated statin therapy. With a mean baseline LDL-C level of 134 mg/ dL, and assuming a 50% reduction in LDL-C from intensive statin therapy, suggests that many participants in the SPIRE-2 trial likely started with untreated LDL-C levels ≥190 mg/dL.…”

mentioning

confidence: 99%

Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above

et al. 2017

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BACKGROUND:Patients with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL are at a higher risk of atherosclerotic cardiovascular disease as a result of long-term exposure to markedly elevated LDL-C levels. Therefore, initiation of statin therapy is recommended for these individuals. However, there is a lack of randomized trial evidence supporting these recommendations in primary prevention. In the present analysis, we provide hitherto unpublished data on the cardiovascular effects of LDL-C lowering among a primary prevention population with LDL-C ≥190 mg/dL. METHODS:We aimed to assess the benefits of LDL-C lowering on cardiovascular outcomes among individuals with primary elevations of LDL-C ≥190 mg/dL without preexisting vascular disease at baseline. We performed post hoc analyses from the WOSCOPS (West of Scotland Coronary Prevention Study) randomized, placebo-controlled trial, and observational posttrial long-term follow-up, after excluding individuals with evidence of vascular disease at baseline. WOSCOPS enrolled 6595 men aged 45 to 64 years, who were randomly assigned to pravastatin 40 mg/d or placebo. In the present analyses, 5529 participants without evidence of vascular disease were included, stratified by LDL-C levels into those with LDL-C <190 mg/dL (n=2969; mean LDL-C 178±6 mg/dL) and those with LDL-C ≥190 mg/dL (n=2560; mean LDL-C 206±12 mg/dL). The effect of pravastatin versus placebo on coronary heart disease and major adverse cardiovascular events were assessed over the 4.9-year randomized controlled trial phase and on mortality outcomes over a total of 20 years of follow-up. RESULTS:Among 5529 individuals without vascular disease, pravastatin reduced the risk of coronary heart disease by 27% (P=0.002) and major adverse cardiovascular events by 25% (P=0.004) consistently among those with and without LDL-C ≥190 mg/dL (P-interaction >0.9). Among individuals with LDL-C ≥190 mg/dL, pravastatin reduced the risk of coronary heart disease by 27% (P=0.033) and major adverse cardiovascular events by 25% (P=0.037) during the initial trial phase and the risk of coronary heart disease death, cardiovascular death, and all-cause mortality by 28% (P=0.020), 25% (P=0.009), and 18% (P=0.004), respectively, over a total of 20 years of follow-up. CONCLUSIONS:The present analyses provide robust novel evidence for the short-and long-term benefits of lowering LDL-C for the primary prevention of cardiovascular disease among individuals with primary elevations of LDL-C ≥190 mg/dL. ORIGINAL RESEARCH ARTICLE P atients with primary elevations of low-density lipoprotein cholesterol (LDL-C) ≥190 mg/dL (to convert values for cholesterol to mmol/L, multiply by 0.02586) are at a higher risk of atherosclerotic cardiovascular disease (ASCVD) as a result of a longterm exposure to markedly elevated LDL-C levels, even in the absence of preexisting ASCVD (ie, primary prevention). Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevat...

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“…Indeed, this variability in LDL-C response to PCSK9 inhibitors seems to occur not only in HoFH but also in those with HeFH 14 and even in individuals with moderate dyslipidemia, after accounting for nongenetic factors such as extremely uncommon antidrug antibodies that are known to attenuate treatment response. 15 Therefore, the ensuing question is because PCSK9 inhibitors reduce LDLR degradation, how do baseline LDLR expression and function modulate the LDL-C lowering effects of these drugs?…”

Section: See Accompanying Article On Page 592mentioning

confidence: 99%

Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab

Cited by 295 publications

References 14 publications

Low-Density Lipoprotein Cholesterol Lowering for the Primary Prevention of Cardiovascular Disease Among Men With Primary Elevations of Low-Density Lipoprotein Cholesterol Levels of 190 mg/dL or Above

Expression of LDLRs (Low-Density Lipoprotein Receptors), Dyslipidemia Severity, and Response to PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Inhibition in Homozygous Familial Hypercholesterolemia

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