Low-Density Lipoprotein Cholesterol–Lowering Effects of AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease in Patients With Heterozygous Familial Hypercholesterolemia

Raal, Frederick J.; Scott, Rob; Somaratne, Ransi; Bridges, Ian; Li, Gang; Wasserman, Scott M.; Stein, Evan A.

doi:10.1161/circulationaha.112.144055

Cited by 472 publications

(316 citation statements)

References 24 publications

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“…A total of 138 study arms from 35 studies were analyzed, comprising 45 539 patients (Table S1). 5, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 Alirocumab was used in 18 studies (28 treatment arms), and evolocumab was used in 17 studies (39 treatment arms; Figure 1); placebo was the most common control used (52 control arms), with ezetimibe used in 17 arms, and standard therapy in 2 arms. Eight studies were of an exclusively FH population, and 5 studies included only patients intolerant to statins.…”

Section: Resultsmentioning

confidence: 99%

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Karatasakis

Danek

Karácsonyi

et al. 2017

JAHA

163

104

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BackgroundWe sought to examine the efficacy and safety of 2 PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: alirocumab and evolocumab.Methods and ResultsWe performed a systematic review and meta‐analysis of randomized controlled trials comparing treatment with and without PCSK9 inhibitors; 35 randomized controlled trials comprising 45 539 patients (mean follow‐up: 85.5 weeks) were included. Mean age was 61.0±2.8 years, and mean baseline low‐density lipoprotein cholesterol was 106±22 mg/dL. Compared with no PCSK9 inhibitor therapy, treatment with a PCSK9 inhibitor was associated with a lower rate of myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64–0.81]; P<0.001), stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67–0.96]; P=0.02), and coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71–0.86]; P<0.001). Overall, no significant change was observed in all‐cause mortality (OR: 0.71 [95% CI, 0.47–1.09]; P=0.12) or cardiovascular mortality (OR: 1.01 [95% CI, 0.85–1.19]; P=0.95). A significant association was observed between higher baseline low‐density lipoprotein cholesterol and benefit in all‐cause mortality (P=0.038). No significant change was observed in neurocognitive adverse events (OR: 1.12 [95% CI, 0.88–1.42]; P=0.37), myalgia (OR: 0.95 [95% CI, 0.75–1.20]; P=0.65), new onset or worsening of preexisting diabetes mellitus (OR: 1.05 [95% CI, 0.95–1.17]; P=0.32), and increase in levels of creatine kinase (OR: 0.84 [95% CI, 0.70–1.01]; P=0.06) or alanine or aspartate aminotransferase (OR: 0.96 [95% CI, 0.82–1.12]; P=0.61).ConclusionsTreatment with a PCSK9 inhibitor is well tolerated and improves cardiovascular outcomes. Although no overall benefit was noted in all‐cause or cardiovascular mortality, such benefit may be achievable in patients with higher baseline low‐density lipoprotein cholesterol.

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Section: Resultsmentioning

confidence: 99%

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Karatasakis

Danek

Karácsonyi

et al. 2017

JAHA

163

104

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“…The RUTHERFORD study (33) showed more reduction of TC in comparison to other studies. The included patients were HeFH with statin therapy.…”

Section: Discussionmentioning

confidence: 55%

“…The summary for the standardized effect size of mean differences of % change from baseline at the end of the study for the Ratio of TC to HDL-C in FH patients "∆Ratio of TC to HDL-C" for evolocumab therapy for seven included studies comparing to placebo (29)(30)(31)(32)(33)(34)36) was -39.14 with 95% CI= -43.34 to -34.95 (P< 0.0001, Figure 4a). The Cochrane Q test for heterogeneity indicated that the studies are heterogeneous (P= 0.0002), I² (inconsistency) of 77% with 95% CI= 41% to 87.4% and could not be combined, thus the random effects for individual and summary of effect size for standardized mean differences was applied.…”

Section: Ratio Of Tc To Hdl-c Effect Of Evolocumab In Comparison To Pmentioning

confidence: 99%

Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials

et al. 2017

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-Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a member of regulatory serine proteases which is mostly expressed in liver. In the physiological condition, LDL-C binds to LDL receptors (LDLRs) and via endocytosis, LDLRs are degraded. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of extracellular LDLRs, and then physiological recycling of LDLRs from surface of liver is cancelled, resulting in elevation of circulating LDL-C in plasma. To evaluate whether evolucomab, as PCSK9 inhibitor monoclonal antibody, ameliorates lipid profile in familial hypercholesterolemia (FH) patients, this meta-analysis has been conducted. PubMed, Web of Science (ISI) and Scopus databases were searched for studies which had investigated the efficacy of evolucomab. Types of outcome investigated were percentage changes from baseline of the lipid profile. Our meta-analysis shows that evolucomab at the dosage of 420 mg monthly could decrease LDL-C by 54.71%, TC by 35.08%, VLDL-C by 28.37 %, ratio of TC to HDL-C by 39.14 %, triglycerides by 12.11 %, and increased HDL-C by 6.06% from baseline compared to placebo at the end of study in FH patients. Our findings indicate that evolocumab could be a hopeful agent for challenging patients, such as statin intolerance or patients who fail to attain the target goal of LDL-C despite consumption of maximum doses of statins.

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“…These patients include those with an inadequate response to high potency statins or those intolerant to statin therapy either at any dose, or at a higher dose, required for adequate LDL-C lowering. Based on early clinical reports, PCSK9 monoclonal antibodies appear generally safe and capable of addressing important limitations of contemporary lipidlowering therapy [4,[6][7][8][10][11][12][13][14].…”

Section: Discussionmentioning

confidence: 99%

Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

Koren

Roth

McKenney

et al. 2015

Postgraduate Medicine

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Background. Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/ kexin type 9, is in Phase III development for the treatment of hypercholesterolemia. In Phase II studies, 150 mg every 2 weeks (Q2W) was the highest Q2W dose studied, and it is currently the highest Q2W dose under development. To better assess the safety and efficacy of this dose, data across three Phase II studies were pooled. Methods. We analyzed data from three double-blind, randomized, placebo-controlled Phase II studies of 8 or 12 weeks' duration. In the current analysis, 77 patients were randomized to the control group and 108 were randomized to alirocumab 150 mg Q2W administered via a single 1 mL subcutaneous injection. Results. Adverse events (AEs) occurred in 58.3% of alirocumab patients compared with 54.5% of placebo-controlled patients. The most common AE was mild, transient injection-site reactions. No signal for muscle symptoms such as myalgia and no cases of neurocognitive effects were reported or observed. One alirocumab patient, also receiving atorvastatin 80 mg/day, had an increase in aspartate transaminase 3 to 5 times the upper limit of normal. Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) from baseline by 68.4% compared with 10.5% for the control group. More than 90% of patients achieved an LDL-C target of < 70 mg/dL with alirocumab versus 8% with control. Marked reductions in other atherogenic lipids and modest increases in high-density lipoprotein cholesterol were also observed. Conclusion. At the highest Q2W dose under development (150 mg), alirocumab appears well tolerated and produces robust LDL-C reductions. These data suggest that alirocumab 150 mg Q2W is an appropriate dose for further evaluation in Phase III trials.

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Low-Density Lipoprotein Cholesterol–Lowering Effects of AMG 145, a Monoclonal Antibody to Proprotein Convertase Subtilisin/Kexin Type 9 Serine Protease in Patients With Heterozygous Familial Hypercholesterolemia

Cited by 472 publications

References 24 publications

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials

Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis

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