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

Article (PDF Available)inNew England Journal of Medicine 370(19) · March 2014with154 Reads
DOI: 10.1056/NEJMoa1316222 · Source: PubMed
Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: 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 ClinicalTrials.gov number, NCT01516879.).
    • "Monoclonal antibodies self-administered in the homeuse setting are relatively new for the treatment of hypercholesterolemia (Rader and Kastelein 2014). The LDL-C reduction and safety profile observed with PCSK9 inhibition [55–75 % in the evolocumab clinical program (Koren et al. 2014; Raal et al. 2015; Robinson et al. 2014; Stroes et al. 2014; Sabatine et al. 2015; Blom et al. 2014)] presents compelling reason for eligible patients to initiate home-use administration of an injectable medication. Moreover, subcutaneously-injected biologics are widely used by patients with diseases such as rheumatoid arthritis , psoriasis, and osteoporosis in the home-use setting "
    [Show abstract] [Hide abstract] ABSTRACT: Evolocumab has been shown to consistently reduce low-density lipoprotein cholesterol (LDL-C) across populations. The phase 3 studies included administration in the home-use and in-clinic settings but did not specifically evaluate the feasibility of home-use administration. Two clinical studies enrolled patients with hypercholesterolemia or mixed dyslipidemia on statin therapy and with/without ezetimibe received evolocumab in the home-use setting. Patients were randomized to self-administer evolocumab using one of two injection devices biweekly over 6 weeks (autoinjector or prefilled syringe; n = 149; ClinicalTrials.gov, NCT01849497) or monthly over 12 weeks (autoinjector or automated minidoser; n = 164; NCT01879319). The first self-administration occurred in the in-clinic setting, and two more were performed in the at-home setting. Patients were successful in self-administering evolocumab in the home-use setting in approximately 95 % of attempts and experienced LDL-C reductions from baseline to week 6 or the mean of weeks 10 and 12 of approximately 65 %. Rates of successful self-administration and LDL-C reduction were similar across dosing schedules and study devices. Adverse events were similar between randomized groups and generally mild in severity. In two clinical studies, therefore, patients were able to successfully self-administer evolocumab in both the in-clinic and at-home settings regardless of which dosing schedule or device they used. Electronic supplementary material The online version of this article (doi:10.1186/s40064-016-1892-3) contains supplementary material, which is available to authorized users.
    Full-text · Article · Dec 2016
    • "Beachtung findetaucheine Lp(a)-Senkung um 28 % mit Evolocumab, z. B. in der DESCARTES-Studie [11], oder um 29 % mit Alirocumab in der ODYSSEY- LONG-TERM-Studie [12]. Die klinische Bedeutung der Lp(a)-Beeinflussung ist noch nicht klar. "
    [Show abstract] [Hide abstract] ABSTRACT: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is of critical importance in the regulation of the low-density lipoprotein (LDL) receptor-mediated metabolism of cholesterol. The discovery of mutations in the gene encoding PCSK9 in families with an autosomal dominant form of familial hypercholesterolemia (FH), which were later shown to be „gain-of-function“ mutations, led to the development of antibodies against PCSK9. The efficacy in markedly reducing levels of LDL-cholesterol and preliminary evidence for benefits in the prevention of cardiovascular diseases indicated that special groups of patients can be more effectively treated. This includes forms of hypercholesterolemia refractory to conventional treatment as well as patients with FH and/or statin intolerance. Further information on long-term efficacy, tolerability and cost-effectiveness of PCSK9 inhibition and possibilities of implementation in the healthcare system are awaited from ongoing clinical outcome trials, such as FOURIER, ODYSSEY OUTCOMES, SPIRE 1 and 2 involving more than 70,000 high-risk patients.
    Full-text · Article · May 2016
    • "Subcutaneous evolocumab was well tolerated in patients with primary hypercholesterolemia or mixed dyslipidemia [22, 23, 25, 26, 33] and homozygous familial hyper- cholesterolemia [36], including in patients aged C65 or C75 years [39]. In a pooled safety analysis (available as an abstract and poster) of data from phase II1718192021 and phase III [12, 22, 23, 25, 26, 31, 32] trials, adverse events were reported in 51.1 % of evolocumab recipients (n = 3946) and in 50.0 % of controls (placebo or ezetimibe; n = 2080), with adverse events leading to study drug discontinuation reported in 1.9 and 2.3 % of patients in the corresponding treatment groups [40]. The most commonly reported adverse events included nasopharyngitis (5.9 % of evolocumab recipients vs. 4.8 % of controls), upper respiratory tract infection (3.2 vs. 2.7 %), headache (3.0 vs. 3.2 %), back pain (3.0 vs. 2.7 %), and myalgia (2.5 vs. 2.6 %). "
    [Show abstract] [Hide abstract] ABSTRACT: Evolocumab (Repatha(®)) is a monoclonal antibody targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered subcutaneously at a dosage of 140 mg every 2 weeks or 420 mg once monthly. Across 12-week phase III trials in patients with primary hypercholesterolemia or mixed dyslipidemia, evolocumab was more effective than placebo (treatment difference -54.8 to -76.3 %) and/or ezetimibe (treatment difference -36.9 to -47.2 %) at reducing low-density lipoprotein cholesterol (LDL-C) levels, including when added to statin therapy, when administered to statin-intolerant patients, when administered as monotherapy, and in patients with heterozygous familial hypercholesterolemia who were receiving statins with or without other lipid-lowering drugs. Evolocumab also significantly lowered LDL-C levels (treatment difference of ≈30 % vs. placebo) in patients with homozygous familial hypercholesterolemia when added to statins with or without ezetimibe in a 12-week phase III trial. The efficacy of evolocumab was maintained in the longer term, and it was well tolerated. In conclusion, subcutaneous evolocumab is a valuable new treatment for use in primary hypercholesterolemia or mixed dyslipidemia and homozygous familial hypercholesterolemia, particularly in patients unable to reach LDL-C goals despite treatment with statins with or without other lipid-lowering therapies and in patients who do not tolerate or are not able to receive statins.
    Article · Dec 2015
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