Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels

Dias, Clapton; Shaywitz, Adam J.; Wasserman, Scott M.; Smith, Brian P.; Gao, Bing; Stolman, Dina; Crispino, Caroline; Smirnakis, Karen; Emery, Maurice G.; Colbert, Alexander; Gibbs, John P.; Retter, Marc W.; Cooke, Blaire; Uy, Stephen; Matson, Mark; Stein, Evan A.

doi:10.1016/j.jacc.2012.08.986

Cited by 217 publications

(58 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mean unbound exposures and the observed relatively large variability in the healthy participants from this study were consistent with results from previously conducted single‐dose studies in healthy volunteers 17. Considerable overlap in the C max and AUC values was observed between healthy subjects and those with hepatic impairment (Figure 2).…”

Section: Discussionsupporting

confidence: 90%

“…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%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 88%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…15,20-24 The magnitude of the lowering of the LDL cholesterol level that we found with inclisiran was generally similar to that observed previously with anti-PCSK9 antibodies 20-24 or intensive statin therapy. 25 However, inclisiran differs mechanistically from anti-PCSK9 antibodies.…”

Section: Discussionsupporting

confidence: 89%

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

et al. 2017

View full text Add to dashboard Cite

BACKGROUND Inclisiran (ALN-PCSsc) is a long-acting RNA interference (RNAi) therapeutic agent that inhibits the synthesis of proprotein convertase subtilisin–kexin type 9 (PCSK9), a target for the lowering of low-density lipoprotein (LDL) cholesterol. METHODS In this phase 1 trial, we randomly assigned healthy volunteers with an LDL cholesterol level of at least 100 mg per deciliter in a 3:1 ratio to receive a subcutaneous injection of inclisiran or placebo in either a single-ascending-dose phase (at a dose of 25, 100, 300, 500, or 800 mg) or a multiple-dose phase (125 mg weekly for four doses, 250 mg every other week for two doses, or 300 or 500 mg monthly for two doses, with or without concurrent statin therapy); each dose cohort included four to eight participants. Safety, the side-effect profile, and pharmacodynamic measures (PCSK9 level, LDL cholesterol level, and exploratory lipid variables) were evaluated. RESULTS The most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. All the adverse events were mild or moderate in severity. There were no serious adverse events or discontinuations due to adverse events. There was one grade 3 elevation in the γ-glutamyltransferase level, which was considered by the investigator to be related to statin therapy. In the single-dose phase, inclisiran doses of 300 mg or more reduced the PCSK9 level (up to a least-squares mean reduction of 74.5% from baseline to day 84), and doses of 100 mg or more reduced the LDL cholesterol level (up to a least-squares mean reduction of 50.6% from baseline). Reductions in the levels of PCSK9 and LDL cholesterol were maintained at day 180 for doses of 300 mg or more. All multiple-dose regimens reduced the levels of PCSK9 (up to a least-squares mean reduction of 83.8% from baseline to day 84) and LDL cholesterol (up to a least-squares mean reduction of 59.7% from baseline to day 84). CONCLUSIONS In this phase 1 trial, no serious adverse events were observed with inclisiran. Doses of 300 mg or more (in single or multiple doses) significantly reduced levels of PCSK9 and LDL cholesterol for at least 6 months. (Funded by Alnylam Pharmaceuticals and the Medicines Company; ClinicalTrials.gov number, NCT02314442.)

show abstract

“…HDL levels in patients with PCSK9 mutations are generally increased[75-77] and most placebo-controlled trials of PCSK9 inhibitors have shown modest increases in HDL levels. [78-82] Furthermore, plasma levels of PCSK9 are associated with plasma apoM levels. [64]…”

Section: Discussionmentioning

confidence: 99%

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Manichaikul¹,

Wilk²,

Ahmed³

et al. 2013

European Respiratory Journal

View full text Add to dashboard Cite

Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD. We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema. We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema. These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.

show abstract

Effects of AMG 145 on Low-Density Lipoprotein Cholesterol Levels

Cited by 217 publications

References 18 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

A Highly Durable RNAi Therapeutic Inhibitor of PCSK9

APOM and high-density lipoprotein cholesterol are associated with lung function and per cent emphysema

Contact Info

Product

Resources

About