AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy

Desai, Nihar R.; Kohli, Payal; Giugliano, Robert P.; O’Donoghue, Michelle L.; Somaratne, Ransi; Zhou, Jing; Hoffman, Elaine; Huang, Fannie; Rogers, William J.; Wasserman, Scott M.; Scott, Robert C.; Sabatine, Marc S.

doi:10.1161/circulationaha.113.001969

Cited by 157 publications

(60 citation statements)

References 33 publications

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“…This observation is consistent with the dose‐response relationship observed in the phase 2 MENDEL and LAPLACE studies, where the 140‐mg Q2W dose of evolocumab approached the flat upper part of the dose‐response curve 5, 31. For example, in the LAPLACE study, a 30% increase in evolocumab dose from 105 mg SC Q2W to 140 mg SC Q2W resulted in an additional ∼5% reduction in LDL‐C at week 12 5. As a consequence, changes to the LDL‐C‐lowering effect are relatively insensitive to changes in pharmacokinetics.…”

Section: Discussionsupporting

confidence: 88%

“…The timing and magnitude of LDL‐C lowering after a dose of evolocumab were consistent with those seen in other studies in patients and healthy volunteers 5, 6, 8, 17, 31. For example, the randomized, double‐blind, placebo‐controlled, phase 2 MENDEL study showed that monotherapy with evolocumab 140 mg Q2W in 45 patients with hypercholesterolemia (baseline LDL‐C 3.6 mmol/L) reduced LDL‐C from baseline by 51% (95% CI –56% to –46%) after 12 weeks of treatment 31.…”

Section: Discussionsupporting

confidence: 88%

“…The magnitude of mean lower exposure with the expected robust LDL‐C and PCSK9 reductions observed in this study indicates that any real pharmacokinetic changes were of little clinical significance. This observation is consistent with the dose‐response relationship observed in the phase 2 MENDEL and LAPLACE studies, where the 140‐mg Q2W dose of evolocumab approached the flat upper part of the dose‐response curve 5, 31. For example, in the LAPLACE study, a 30% increase in evolocumab dose from 105 mg SC Q2W to 140 mg SC Q2W resulted in an additional ∼5% reduction in LDL‐C at week 12 5.…”

Section: Discussionsupporting

confidence: 85%

“…It acts as a major regulator of circulating low‐density lipoprotein cholesterol (LDL‐C) by binding to hepatic cell surface LDL‐C receptors, directing LDL‐C receptors for degradation, and thereby reducing the clearance of LDL‐C particles 4. Through its PCSK9‐lowering effect, administration of evolocumab increases the density of LDL‐C receptors and significantly reduces LDL‐C levels in patients with hypercholesterolemia 4, 5. In several clinical trials up to 52 weeks in duration, the safety and tolerability profile of evolocumab was similar to that of placebo 6, 7, 8, 9, 10…”

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confidence: 99%

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Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Gibbs

Slatter

Egbuna

et al. 2016

The Journal of Clinical Pharma

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Evolocumab binds PCSK9, increasing low‐density lipoprotein cholesterol (LDL‐C) receptors and lowering LDL‐C. Target‐mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL‐C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. An open‐label, parallel‐group study evaluated the pharmacokinetics of evolocumab in hepatic‐impaired (Child‐Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group) and received a single 140‐mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made predose and postdose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time course of PCSK9 or LDL‐C reduction was observed despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere‐Terpstra trend test; maximum serum concentration P = .18; area under the curve P = .09). Maximum reductions were observed in moderately impaired subjects vs healthy individuals: mean maximum serum concentration –34%; mean area under the concentration‐time curve (AUC) –47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL‐C reductions in the healthy, mild, and moderate groups were –57% (–64% to –48%), –70% (–75% to –63%), and –53% (–61% to –43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Gibbs

Slatter

Egbuna

et al. 2016

The Journal of Clinical Pharma

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“…PCSK9 binds to the LDL-receptor thereby making it to a target of lysosomal degradation. Inhibitors of PCSK9 decrease Lp(a) levels up to 32% 16 and belong to the very promising drugs for future lipid-lowering therapies in case it will be demonstrated that they also lower clinical endpoints. Therapies that have a significant Lp(a)-lowering effect result in many cases also in substantial changes of other risk factors.…”

Section: February 11 2014mentioning

confidence: 99%

Lipoprotein(a)

Kronenberg

2014

Circulation

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When the first prospective studies on lipoprotein(a) [Lp(a)] were published in the early 1990s, the career of Lp(a) as a risk factor for cardiovascular disease (CVD) was almost stopped right at its beginning. A few of these prospective studies were negative 1 and resulted in a major discussion whether Lp(a) had its best times already behind it. However, numerous later studies and meta-analysis of the data strengthened the association between high Lp(a) concentrations and CVD.2 Finally, genetic research on Lp(a) became the basis for what revolutionized epidemiological research during the last decade in general. This is based on the observation that Lp(a) concentrations are largely determined by a copy number variation in the LPA gene, which results in an interindividually highly variable and large number of so-called kringle-IV repeats of the apolipoprotein(a) [apo(a)] protein. This polymorphism explains between 30% and 70% of the Lp(a) concentrations, which makes Lp(a) to the lipoprotein with the strongest genetic determination.3 Individuals with a low number of kringle-IV repeats (small isoform carriers) have on average markedly higher Lp(a) concentrations. 4 Because the number of kringle-IV repeats are subject of inheritance, it is already determined at the time of conception whether one inherits apo(a) isoforms associated with high or low Lp(a) concentrations. Consequently, those who inherit small isoforms are exposed life-long to high Lp(a) concentrations and are expected to have a high CVD risk. This was indeed the case when the first studies using this concept were published in the early 1990s. They demonstrated that individuals carrying small isoforms have indeed a high CVD risk.5 Studies using SNPs that tag a subfraction of the small apo(a) isoforms took the same line. 6 This concept using genetic variants that determine an important fraction of the risk factor under suspicion to demonstrate an association with the outcome of interest was later called Mendelian Randomization.7 It was a major step not only for Lp(a) research but for epidemiology in general because usually epidemiological studies can hardly prove causality. However, the Mendelian randomization concept can provide a very strong support of causality. With the help of this concept several risk factors have been reevaluated and some of them changed their status from a risk factor to a risk marker that is not necessarily involved in the causal chain of the disease. For Lp(a) it was even a starting point because all of a sudden it became an interesting object for intervention. Article see p 635In the past it was discussed controversially whether high Lp(a) concentrations are only a risk factor when also other well-known CVD risk factors are present in an individual. In this issue of Circulation, Khera et al 8 investigated whether Lp(a) is a significant determinant of residual CVD risk in the JUPITER trial that recruited individuals without a history of CVD at baseline, with low-density lipoprotein (LDL)-cholesterol <130 mg/dL and a high-sensitiv...

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Long-term Low-Density Lipoprotein Cholesterol–Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia

et al. 2017

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AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy

Cited by 157 publications

References 33 publications

Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Evaluation of Evolocumab (AMG 145), a Fully Human Anti‐PCSK9 IgG2 Monoclonal Antibody, in Subjects With Hepatic Impairment

Lipoprotein(a)

Long-term Low-Density Lipoprotein Cholesterol–Lowering Efficacy, Persistence, and Safety of Evolocumab in Treatment of Hypercholesterolemia

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