A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia

New England Journal of Medicine (Impact Factor: 55.87). 03/2014; 370(19). DOI: 10.1056/NEJMoa1316222
Source: PubMed


Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in phase 2 studies. We conducted a phase 3 trial to evaluate the safety and efficacy of 52 weeks of treatment with evolocumab.

We stratified patients with hyperlipidemia according to the risk categories outlined by the Adult Treatment Panel III of the National Cholesterol Education Program. On the basis of this classification, patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a run-in period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. The primary end point was the percent change from baseline in LDL cholesterol, as measured by means of ultracentrifugation, at week 52.

Among the 901 patients included in the primary analysis, the overall least-squares mean (±SE) reduction in LDL cholesterol from baseline in the evolocumab group, taking into account the change in the placebo group, was 57.0±2.1% (P<0.001). The mean reduction was 55.7±4.2% among patients who underwent background therapy with diet alone, 61.6±2.6% among those who received 10 mg of atorvastatin, 56.8±5.3% among those who received 80 mg of atorvastatin, and 48.5±5.2% among those who received a combination of 80 mg of atorvastatin and 10 mg of ezetimibe (P<0.001 for all comparisons). Evolocumab treatment also significantly reduced levels of apolipoprotein B, non-high-density lipoprotein cholesterol, lipoprotein(a), and triglycerides. The most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza, and back pain.

At 52 weeks, evolocumab added to diet alone, to low-dose atorvastatin, or to high-dose atorvastatin with or without ezetimibe significantly reduced LDL cholesterol levels in patients with a range of cardiovascular risks. (Funded by Amgen; DESCARTES number, NCT01516879.).

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Available from: Dirk Blom, Sep 14, 2015
    • "Additionally, putative interactions with kinases such as Yes1 and SLK were enhanced, suggesting some activation of downstream signaling is preferentially present in Comb-NPC1L1 versus WT- NPC1L1 proteome when treated with ezetimibe. Interestingly, identification of loss-of-function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) resulted in a significant reduction in LDL-cholesterol levels and a reduced risk for cardiovascular event[46], and these data led to the development of monoclonal antibodies which inhibit PCSK9 and significantly reduce LDL-cholesterol levels[47]. Hopefully, our more expansive approach to analyzing this exceptional responder will ultimately lead to the development of more potent inhibitors of NPC1L1 that would lead to a further reduction in LDL-cholesterol levels and subsequent cardiovascular events. "
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    ABSTRACT: Background: Strategies to reduce LDL-cholesterol involve reductions in cholesterol synthesis or absorption. We identified a familial hypercholesterolemia patient with an exceptional response to the cholesterol absorption inhibitor, ezetimibe. Niemann-Pick C 1-like 1 (NPC1L1) is the molecular target of ezetimibe. Methods and results: Sequencing identified nucleotide changes predicted to change amino acids 52 (L52P), 300 (I300T) and 489 (S489G) in exceptional NPC1L1. In silico analyses identified increased stability and cholesterol binding affinity in L52P-NPC1L1 versus WT-NPC1L1. HEK293 cells overexpressing WT-NPC1L1 or NPC1L1 harboring amino acid changes singly or in combination (Comb-NPC1L1) had reduced cholesterol uptake in Comb-NPC1L1 when ezetimibe was present. Cholesterol uptake was reduced by ezetimibe in L52P-NPC1L1, I300T-NPC1L1, but increased in S489G-NPC1L1 overexpressing cells. Immunolocalization studies found preferential plasma membrane localization of mutant NPC1L1 independent of ezetimibe. Flotillin 1 and 2 expression was reduced and binding to Comb-NPC1L1 was reduced independent of ezetimibe exposure. Proteomic analyses identified increased association with proteins that modulate intermediate filament proteins in Comb-NPC1L1 versus WT-NPC1L1 treated with ezetimibe. Conclusion: This is the first detailed analysis of the role of NPC1L1 mutations in an exceptional responder to ezetimibe. The results point to a complex set of events in which the combined mutations were shown to affect cholesterol uptake in the presence of ezetimibe. Proteomic analysis suggests that the exceptional response may also lie in the nature of interactions with cytosolic proteins.
    No preview · Article · Dec 2015 · Atherosclerosis
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    • "Thus, lowering levels of LDL-C through PCSK9 inhibition together with statins has been considered as an attractive and promising pharmaceutical approach (Cariou et al., 2011; Farnier, 2013). In order to reach this goal, human monoclonal antibodies (mAbs) directed against PCSK9 were developed for clinical applications and recent Phase 3 trials showed a strong reduction (up to 60%) of plasma LDL-C concentrations in various hypercholesterolemic patients treated with anti-PCSK9 mAb (Blom et al., 2014; Cannon et al., 2015; Cariou et al., 2011; Farnier, 2013; Roth and Diller, 2014). "
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    ABSTRACT: Proprotein convertase subtilisin kexin type 9 (PCSK9) is a critical modulator of cholesterol homeostasis. Whereas PCSK9 gain-of-function (GOF) mutations are associated with autosomal dominant hypercholesterolemia (ADH) and premature atherosclerosis, PCSK9 loss-of-function (LOF) mutations have a cardio-protective effect and in some cases can lead to familial hypobetalipoproteinemia (FHBL). However, limitations of the currently available cellular models preclude deciphering the consequences of PCSK9 mutation further. We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL. To achieve our goal, urine-sample-derived somatic cells were reprogrammed into hiPSCs by using episomal vectors. UhiPSC were efficiently differentiated into hepatocyte-like cells (HLCs). Compared to control cells, cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (P<0.001) of low-density lipoprotein (LDL) uptake, whereas cells originally derived from an individual with FHBL (HLC-R104C/V114A) displayed a strong decrease in PCSK9 secretion (-89.7%; P<0.001) and had a 106% increase (P=0.0104) of LDL uptake. Pravastatin treatment significantly enhanced LDL receptor (LDLR) and PCSK9 mRNA gene expression, as well as PCSK9 secretion and LDL uptake in both control and S127R HLCs. Pravastatin treatment of multiple clones led to an average increase of LDL uptake of 2.19±0.77-fold in HLC-S127R compared to 1.38±0.49 fold in control HLCs (P<0.01), in line with the good response to statin treatment of individuals carrying the S127R mutation (mean LDL cholesterol reduction=60.4%, n=5). In conclusion, urine samples provide an attractive and convenient source of somatic cells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function.
    Full-text · Article · Nov 2015 · Disease Models and Mechanisms
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    ABSTRACT: To summarize the therapeutic strategies to inhibit PCSK9 and to describe the main results obtained in phase I and II trials with monoclonal antibodies targeting PCSK9. Among the various approaches for PCSK9 inhibition, human data are only available for inhibition of PCSK9 binding to LDL receptor by monoclonal antibodies. Promising preclinical studies have also been reported with other strategies, including inhibition of PCSK9 synthesis by gene silencing agents. The two most advanced monoclonal antibodies in development are SAR236553/REGN727 and AMG145. In phase II, these two monoclonal antibodies administered subcutaneously are well tolerated and effective to decrease atherogenic lipoproteins. A dramatic decrease in LDL cholesterol up to 70% can be obtained. The efficacy has been evaluated so far in addition to statins in hypercholesterolemic patients with or without familial hypercholesterolemia, in patients with intolerance to statin therapy and in monotherapy. The short-term efficacy, safety and tolerability of two monoclonal antibodies to PSCK9 have been demonstrated in several phase II trials. These PCSK9 inhibitors are now tested in larger phase III studies to provide insights into the long-term safety and clinical efficacy of this very promising approach.
    No preview · Article · Jun 2013 · Current opinion in lipidology
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