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 ClinicalTrials.gov number, NCT01516879.).
Summary Background Homozygous familial hypercholesterolaemia is a rare, serious disorder caused by very low or absent plasma clearance of LDL, substantially raised LDL cholesterol, and accelerated ...development of cardiovascular disease. Conventional lipid-lowering treatments are modestly effective. Evolocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), reduced LDL cholesterol by 16% in a pilot study. We now report results with evolocumab in a randomised, double-blind, placebo-controlled phase 3 trial. Methods This randomised, double-blind, placebo-controlled phase 3 trial was undertaken at 17 sites in ten countries in North America, Europe, the Middle East, and South Africa. 50 eligible patients (aged ≥12 years) with homozygous familial hypercholesterolaemia, on stable lipid-regulating therapy for at least 4 weeks, and not receiving lipoprotein apheresis, were randomly allocated by a computer-generated randomisation sequence in a 2:1 ratio to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks. Randomisation was stratified by LDL cholesterol at screening (<11 mmol/L or ≥11 mmol/L) and implemented by a computerised interactive voice-response system. Patients, study personnel, and the funder were masked to treatment and to the efficacy results by the central laboratory not returning LDL cholesterol or any lipid results to the clinical sites after the baseline visit. The primary endpoint was percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov , number NCT01588496. Findings Of the 50 eligible patients randomly assigned to the two treatment groups, 49 actually received the study drug and completed the study (16 in the placebo group and 33 in the evolocumab group). Compared with placebo, evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 weeks by 30·9% (95% CI −43·9% to −18·0%; p<0·0001). Treatment-emergent adverse events occurred in ten (63%) of 16 patients in the placebo group and 12 (36%) of 33 in the evolocumab group. No serious clinical or laboratory adverse events occurred, and no anti-evolocumab antibody development was detected during the study. Interpretation In patients with homozygous familial hypercholesterolaemia receiving stable background lipid-lowering treatment and not on apheresis, evolocumab 420 mg administered every 4 weeks was well tolerated and significantly reduced LDL cholesterol compared with placebo. Funding Amgen Inc.
Evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9), significantly reduced low-density lipoprotein (LDL) cholesterol levels in short-term studies. We ...conducted two extension studies to obtain longer-term data.
In two open-label, randomized trials, we enrolled 4465 patients who had completed 1 of 12 phase 2 or 3 studies ("parent trials") of evolocumab. Regardless of study-group assignments in the parent trials, eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Patients were followed for a median of 11.1 months with assessment of lipid levels, safety, and (as a prespecified exploratory analysis) adjudicated cardiovascular events including death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and heart failure. Data from the two trials were combined.
As compared with standard therapy alone, evolocumab reduced the level of LDL cholesterol by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P<0.001). Most adverse events occurred with similar frequency in the two groups, although neurocognitive events were reported more frequently in the evolocumab group. The risk of adverse events, including neurocognitive events, did not vary significantly according to the achieved level of LDL cholesterol. The rate of cardiovascular events at 1 year was reduced from 2.18% in the standard-therapy group to 0.95% in the evolocumab group (hazard ratio in the evolocumab group, 0.47; 95% confidence interval, 0.28 to 0.78; P=0.003).
During approximately 1 year of therapy, the use of evolocumab plus standard therapy, as compared with standard therapy alone, significantly reduced LDL cholesterol levels and reduced the incidence of cardiovascular events in a prespecified but exploratory analysis. (Funded by Amgen; OSLER-1 and OSLER-2 ClinicalTrials.gov numbers, NCT01439880 and NCT01854918.).
Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There ...are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic
mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels.
We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months.
Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P<0.001). Patients receiving volanesorsen had a 77% decrease in mean triglyceride levels, corresponding to a mean decrease of 1712 mg per deciliter (19.3 mmol per liter) (95% confidence interval CI, 1330 to 2094 mg per deciliter 15.0 to 23.6 mmol per liter), whereas patients receiving placebo had an 18% increase in mean triglyceride levels, corresponding to an increase of 92.0 mg per deciliter (1.0 mmol per liter) (95% CI, -301.0 to 486 mg per deciliter -3.4 to 5.5 mmol per liter) (P<0.001). At 3 months, 77% of the patients in the volanesorsen group, as compared with 10% of patients in the placebo group, had triglyceride levels of less than 750 mg per deciliter (8.5 mmol per liter). A total of 20 of 33 patients who received volanesorsen had injection-site reactions, whereas none of the patients who received placebo had such reactions. No patients in the placebo group had platelet counts below 100,000 per microliter, whereas 15 of 33 patients in the volanesorsen group had such levels, including 2 who had levels below 25,000 per microliter. No patient had platelet counts below 50,000 per microliter after enhanced platelet-monitoring began.
Volanesorsen lowered triglyceride levels to less than 750 mg per deciliter in 77% of patients with familial chylomicronemia syndrome. Thrombocytopenia and injection-site reactions were common adverse events. (Funded by Ionis Pharmaceuticals and Akcea Therapeutics; APPROACH Clinical Trials.gov number, NCT02211209.).
Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol ...(LDL-C) goals.
The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH).
In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids.
In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was −21.2% (−59.8 mg/dl) in patients with HoFH and −54.9% (−104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from −19.6% at week 12 to −29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis.
Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.
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Summary Background Patients with homozygous familial hypercholesterolaemia respond inadequately to existing drugs. We aimed to assess the efficacy and safety of the microsomal triglyceride transfer ...protein inhibitor lomitapide in adults with this disease. Methods We did a single-arm, open-label, phase 3 study of lomitapide for treatment of patients with homozygous familial hypercholesterolemia. Current lipid lowering therapy was maintained from 6 weeks before baseline through to at least week 26. Lomitapide dose was escalated on the basis of safety and tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in levels of LDL cholesterol from baseline to week 26, after which patients remained on lomitapide through to week 78 for safety assessment. Percent change from baseline to week 26 was assessed with a mixed linear model. Findings 29 men and women with homozygous familial hypercholesterolaemia, aged 18 years or older, were recruited from 11 centres in four countries (USA, Canada, South Africa, and Italy). 23 of 29 enrolled patients completed both the efficacy phase (26 weeks) and the full study (78 weeks). The median dose of lomitapide was 40 mg a day. LDL cholesterol was reduced by 50% (95% CI −62 to −39) from baseline (mean 8·7 mmol/L SD 2·9) to week 26 (4·3 mmol/L 2·5; p<0·0001). Levels of LDL cholesterol were lower than 2·6 mmol/L in eight patients at 26 weeks. Concentrations of LDL cholesterol remained reduced by 44% (95% CI −57 to −31; p<0·0001) at week 56 and 38% (–52 to −24; p<0·0001) at week 78. Gastrointestinal symptoms were the most common adverse event. Four patients had aminotransaminase levels of more than five times the upper limit of normal, which resolved after dose reduction or temporary interruption of lomitapide. No patient permanently discontinued treatment because of liver abnormalities. Interpretation Our study suggests that treatment with lomitapide could be a valuable drug in the management of homozygous familial hypercholesterolaemia. Funding FDA Office of the Orphan Product Development, Aegerion Pharmaceuticals.
This contemporary, international, evidence-informed guidance aims to achieve the greatest good for the greatest number of people with familial hypercholesterolaemia (FH) across different countries. ...FH, a family of monogenic defects in the hepatic LDL clearance pathway, is a preventable cause of premature coronary artery disease and death. Worldwide, 35 million people have FH, but most remain undiagnosed or undertreated. Current FH care is guided by a useful and diverse group of evidence-based guidelines, with some primarily directed at cholesterol management and some that are country-specific. However, none of these guidelines provides a comprehensive overview of FH care that includes both the lifelong components of clinical practice and strategies for implementation. Therefore, a group of international experts systematically developed this guidance to compile clinical strategies from existing evidence-based guidelines for the detection (screening, diagnosis, genetic testing and counselling) and management (risk stratification, treatment of adults or children with heterozygous or homozygous FH, therapy during pregnancy and use of apheresis) of patients with FH, update evidence-informed clinical recommendations, and develop and integrate consensus-based implementation strategies at the patient, provider and health-care system levels, with the aim of maximizing the potential benefit for at-risk patients and their families worldwide.
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