Long-Term Efficacy of Evolocumab in Patients With or Without Multivessel Coronary Disease.

BACKGROUND: In FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), during a median follow-up of 2.2 years, risk reduction for major adverse cardiovascular event with evolocumab was greater in patients with multivessel disease (MVD). The FOURIER Open-Label Extension (FOURIER-OLE) provides an additional median follow-up of 5 years. OBJECTIVES: The purpose of this study was to assess the long-term benefit of evolocumab in patients with and without MVD. METHODS: FOURIER randomized 27,564 patients to evolocumab vs placebo; 6,635 entered FOURIER-OLE. Patients with coronary artery disease were categorized based on the presence of MVD (≥40% stenosis in ≥2 large vessels). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary endpoint was cardiovascular death, myocardial infarction, or stroke. RESULTS: Of 23,656 patients in FOURIER with coronary artery disease, 25.4% had MVD; 5,887 patients continued into FOURIER-OLE. The risk reduction with initial allocation to evolocumab tended to be greater in patients with MVD than in those without: 23% (HR: 0.77 [95% CI: 0.68-0.87]) vs 11% (HR: 0.89 [95% CI: 0.82-0.96]) for the primary and 31% (HR: 0.69 [95% CI: 0.59-0.81]) vs 15% (HR: 0.85 [95% CI: 0.77-0.94]) for the key secondary endpoints (Pinteraction = 0.062 and Pinteraction = 0.031, respectively). The magnitude of benefit tended to grow during the first several years, reaching 37% to 38% reductions in risk in patients with MVD and 23% to 28% reductions in risk in patients without MVD. CONCLUSIONS: Evolocumab reduced the rate of major adverse cardiovascular event in patients with and without MVD. The benefit tended to occur earlier and was larger in patients with MVD. However, the magnitude grew over time in both groups. These data support early initiation of intensive low-density lipoprotein cholesterol lowering both in patients with and without MVD.

Efficacy and Safety of Evolocumab in Chinese Patients with Primary Hypercholesterolemia and Mixed Dyslipidemia: 12-Week Primary Results of the HUA TUO Randomized Clinical Trial.

INTRODUCTION: Evolocumab, a fully human proprotein convertase/subtilisin kexin type 9 inhibitor antibody, significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes mellitus and hyperlipidemia and mixed dyslipidemia. This 12-week study evaluated the efficacy and safety of evolocumab in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia at different levels of cardiovascular disease risk. METHODS: HUA TUO was a 12-week randomized, double-blind, placebo-controlled study. Chinese patients aged 18 years or older on stable optimized statin therapy were randomized 2:2:1:1 to receive evolocumab 140 mg every 2 weeks (Q2W), evolocumab 420 mg monthly (QM), or a matching placebo. The coprimary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12 and at week 12. RESULTS: Overall, 241 randomized patients (mean [standard deviation] age, 60.2 [10.3] years) received evolocumab 140 mg Q2W (n = 79), evolocumab 420 mg QM (n = 80), placebo Q2W (n = 41), or placebo QM (n = 41). At weeks 10 and 12, the placebo-adjusted least-squares mean percent change from baseline in LDL-C for the evolocumab 140 mg Q2W group was - 70.7% (95% CI - 78.0% to - 63.5%); - 69.7% (95% CI - 76.5% to - 63.0%) for the evolocumab 420 mg QM group. Significant improvements in all other lipid parameters were observed with evolocumab. The patient incidence of treatment-emergent adverse events was similar between the treatment groups and across dosing regimens. CONCLUSION: In Chinese patients with primary hypercholesterolemia and mixed dyslipidemia, 12-week treatment with evolocumab significantly lowered LDL-C and other lipids, and was safe and well tolerated (NCT03433755).

Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Quantification of LDL-Cholesterol Corrected for Molar Concentration of Lipoprotein(a).

PURPOSE: Cholesterol in lipoprotein(a) [Lp(a)-C] is commonly estimated as 30% of the measured Lp(a) mass. However, difficulties in the accurate measurement of Lp(a) mass, along with the inaccuracy of the 30% assumption, produce erroneous values when LDL-C is corrected for Lp(a) [LDL-CLp(a)corr]. Our aim was to develop a new formula for LDL-CLp(a)corr to reduce this error. METHODS: We developed a new formula to calculate Lp(a)-C from the molar measurement of Lp(a), which is Lp(a) nmol/L × 0.077 = Lp(a)-C mg/dL. The calculated Lp(a)-C is subtracted from LDL-C to obtain LDL-CLp(a)corr. The results obtained with our novel formula versus the conventional formula were compared in 440 samples from 239 participants enrolled in the BANTING study. RESULTS: With the conventional formula, approximately 7% of samples with low LDL-C resulted in negative LDL-CLp(a)corr values. With the new formula, no negative LDL-CLp(a)corr values occurred. Among groups with the highest Lp(a)/apoB ratio (p < 0.001) and smaller apolipoprotein(a) isoform size (p < 0.006), LDL-CLp(a)corr was significantly underestimated by the conventional formula, which may result in the undertreatment of some patients. CONCLUSION: The new formula provides more reliable estimates of LDL-CLp(a)corr than the conventional formula. TRIAL REGISTRATION: ClinicalTrials.gov NCT02739984.

Long-Term Evolocumab in Patients With Established Atherosclerotic Cardiovascular Disease.

BACKGROUND: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), the proprotein convertase subtilisin-kexin type 9 inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and risk of cardiovascular events and was safe and well tolerated over a median of 2.2 years of follow-up. However, large-scale, long-term data are lacking. METHODS: The parent FOURIER trial randomized 27 564 patients with atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on statin to evolocumab versus placebo. Patients completing FOURIER at participating sites were eligible to receive evolocumab in 2 open-label extension studies (FOURIER-OLE [FOURIER Open-Label Extension]) in the United States and Europe; primary analyses were pooled across studies. The primary end point was the incidence of adverse events. Lipid values and major adverse cardiovascular events were prospectively collected. RESULTS: A total of 6635 patients were enrolled in FOURIER-OLE (3355 randomized to evolocumab and 3280 to placebo in the parent study). Median follow-up in FOURIER-OLE was 5.0 years; maximum exposure to evolocumab in parent plus FOURIER-OLE was 8.4 years. At 12 weeks in FOURIER-OLE, median LDL-C was 30 mg/dL, and 63.2% of patients achieved LDL-C <40 mg/dL on evolocumab. Incidences of serious adverse events, muscle-related events, new-onset diabetes, hemorrhagic stroke, and neurocognitive events with evolocumab long term did not exceed those for placebo-treated patients during the parent study and did not increase over time. During the FOURIER-OLE follow-up period, patients originally randomized in the parent trial to evolocumab versus placebo had a 15% lower risk of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina or coronary revascularization (hazard ratio, 0.85 [95% CI, 0.75-0.96]; P=0.008); a 20% lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80 [95% CI, 0.68-0.93]; P=0.003); and a 23% lower risk of cardiovascular death (hazard ratio, 0.77 [95% CI, 0.60-0.99]; P=0.04). CONCLUSIONS: Long-term LDL-C lowering with evolocumab was associated with persistently low rates of adverse events for >8 years that did not exceed those observed in the original placebo arm during the parent study and led to further reductions in cardiovascular events compared with delayed treatment initiation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT02867813 and NCT03080935.

Time-averaged low-density lipoprotein cholesterol lowering with evolocumab: Pooled analysis of phase 2 trials.

LDL-C is the pivotal risk factor for atherosclerotic cardiovascular disease, and the benefit from LDL-C lowering is proportional to the magnitude of reduction. Clinical trials demonstrate that evolocumab reduces LDL-C levels by approximately 60% when measured at the trough of drug effect, which may underestimate cumulative LDL-C reduction. We obtained a time-averaged estimate of LDL-C lowering that included both peaks and troughs. Pooled analysis of 5 phase 2 trials included patients with hypercholesterolemia who received placebo or evolocumab (140 mg every 2 weeks [Q2W] or 420 mg monthly [QM]). Percent changes from baseline LDL-C and free serum PCSK9 were averaged across weeks 9-12. In 372 patients, time-averaged percent reduction from baseline in LDL-C with evolocumab vs placebo was 67.6% (95% CI: 63.9-71.3) with Q2W dosing and 65.0% (95% CI: 60.7-69.3) with QM dosing. The time-averaged measure yielded LDL-C reductions for evolocumab that exceeded measurements at the end of dosing intervals and may provide a better estimate of cardiovascular benefit during long-term therapy.

Effects of evolocumab in individuals with type 2 diabetes with and without atherogenic dyslipidemia: An analysis from BANTING and BERSON.

BACKGROUND: Atherogenic dyslipidemia (AD), characterized by increased concentrations of apolipoprotein B (ApoB)-containing particles, is often present in individuals with type 2 diabetes mellitus (T2DM). Non-high-density lipoprotein cholesterol (non-HDL-C), cholesterol transported by apolipoprotein B (ApoB)-containing particles), and total apoB are considered secondary goals of lipid-lowering therapy to guide treatment of residual cardiovascular risk. The BANTING and BERSON studies demonstrated that evolocumab added to statin therapy reduced atherogenic lipid and lipoproteins concentrations in patients with T2DM. METHODS: This post-hoc analysis combined data from two randomized, placebo-controlled trials, BANTING and BERSON, to investigate the effect of evolocumab (140 mg every two weeks [Q2W] or 420 mg monthly [QM]) on atherogenic lipid (LDL-C, non-HDL-C, VLDL-C, remnant cholesterol) and lipoproteins (ApoB, lipoprotein(a) (Lp[a])), and achievement of 2019 European Society of Cardiology/European Atherosclerosis Society lipid treatment goals in individuals with and without AD. RESULTS: In individuals with high TGs with (n = 389) and without (n = 196) AD receiving background statin therapy, evolocumab, compared with placebo, substantially reduced the cholesterol levels from all ApoB atherogenic lipoproteins (least squares (LS) mean LDL-C by 66.7% to 74.3%, non-HDL-C by 53.4% to 65.8%, median remnant cholesterol by 28.9% to 34.2%, VLDL-C by 16.1% to 19.6%) and median TGs levels (by 17.5% to 19.6%) at the mean of weeks 10 and 12. LS mean ApoB was significantly reduced by 41.5% to 56.6% at week 12. Results were consistent in diabetic individuals with normal TGs (n = 519). Evolocumab was also associated with a significant reduction in median Lp(a) by 35.0% to 53.9% at the mean of weeks 10 and 12. A majority (74.7% to 79.8%) of evolocumab-treated individuals achieved the goal of both an LDL-C < 1.4 mmol/L and an LDL-C reduction of at least 50%, > 75% achieved non-HDL-C < 2.2 mmol/L at the mean of weeks 10 and 12, and > 67% achieved ApoB < 65 mg/dL at week 12. CONCLUSIONS: Evolocumab effectively reduced LDL-C, non-HDL-C, ApoB, Lp(a), and remnant cholesterol in individuals with T2DM with and without AD. Evolocumab Q2W or QM enabled most individuals at high/very-high cardiovascular disease risk to achieve their LDL-C, non-HDL-C, and ApoB recommended goals.

Effects of Evolocumab on Low-Density Lipoprotein Cholesterol, Non-High Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a) by Race and Ethnicity: A Meta-Analysis of Individual Participant Data From Double-Blind and Open-Label Extension Studies.

Background Prevalence of cardiovascular disease risk factors and rates of atherosclerotic cardiovascular disease outcomes vary across racial/ethnic groups. This analysis examined the effects of evolocumab on LDL-C (low-density lipoprotein cholesterol) levels and LDL-C goals achievement by race/ethnicity. Methods and Results Data from 15 phase 2 and 3 studies of treatment with evolocumab versus placebo or ezetimibe were pooled (n=7669). Results were analyzed by participant clinical characteristics and by self-identified race/ethnicity. Key outcomes included percent change from baseline in LDL-C, achievement of LDL-C <70 mg/dL, and LDL-C reduction of ≥50% at 12 weeks and at 1 to 5 years. Across 12-week studies, mean percent change in LDL-C from baseline in evolocumab-treated participants was -52% to -59% for White and -46% to -67% for non-White participants, across clinical characteristics groups. LDL-C <70 mg/dL was achieved in 43% to 84% and 62% to 94% and LDL-C reduction of ≥50% in 63% to 78% and 58% to 86%, respectively. In 1- to 5-year studies, mean percent change in LDL-C was -46% to -52% for White and -49% to -55% for non-White participants. LDL-C <70 mg/dL was achieved in 53% to 84% and 66% to 77%, and LDL-C reduction of ≥50% in 53% to 67% and 58% to 68%, respectively. The treatment effect on mean percent change in LDL-C differed only in participants with type 2 diabetes mellitus, with a larger reduction in Asian participants. The qualitative interaction P values were nonsignificant, indicating consistent directionality of effect. Conclusions Similar reduction in LDL-C levels with evolocumab was observed across racial/ethnic groups in 12-week and 1- to 5-year studies. Among those with diabetes mellitus, Asian participants had greater LDL-C reduction.

Pharmacokinetic/pharmacodynamic and safety study of a single dose of evolocumab 140 mg in healthy Chinese subjects.

OBJECTIVE: Evolocumab, a human monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), markedly reduces low-density lipoprotein cholesterol (LDL-C). Here we characterize the pharmacokinetics, pharmacodynamics, safety, and tolerability of evolocumab manufactured at a new site administered in healthy Chinese subjects. MATERIALS AND METHODS: This phase 1 study of a single subcutaneous 140-mg dose of evolocumab was conducted in healthy subjects of Chinese descent residing in Hong Kong. Subjects were followed through day 85. RESULTS: 20 subjects (all men) were enrolled. Mean (SD) age was 26.6 (8.5) years; baseline LDL-C was 2.4 (0.7) mmol/L. Mean (SD) evolocumab maximum serum concentration (Cmax) was 14.1 (5.0) µg/mL; area under the serum drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was 178 (80) day×µg/mL; AUC from time 0 to infinity (AUCinf) was 187 (80) day×µg/mL; terminal half-life was 5.95 (1.76) days; median time to reach Cmax (tmax) was 4.0 days. Maximum LDL-C decrease (-57.5%) was observed on day 15 and recovered to baseline by day 57. The most common adverse events (AEs) were nasal congestion (20%), oropharyngeal pain (15%), sneezing (15%), cough (10%), upper respiratory tract infection (10%), and diarrhea (10%). Most AEs were isolated incidences of mild severity, with no serious or treatment-related events. No anti-evolocumab antibodies were detected. CONCLUSION: A single 140-mg dose of evolocumab manufactured at the new site and administered in healthy Chinese subjects was associated with typical antibody pharmacokinetics, rapid and reversible decreases in LDL-C, and no new safety events.

Effect of Evolocumab on Non-High-Density Lipoprotein Cholesterol, Apolipoprotein B, and Lipoprotein(a): A Pooled Analysis of Phase 2 and Phase 3 Studies.

Background Dyslipidemia guidelines recommend non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B (ApoB) as additional targets of therapy and consider lipoprotein(a) a significant cardiovascular risk marker. The current analysis evaluates the effects of evolocumab on these parameters in various patient populations over time. Methods and Results Data from 7690 patients, 4943 of whom received at least 1 dose of evolocumab, in 15 phase 2 and phase 3 studies with a duration ranging from 12 weeks to 5 years were pooled based on study length, patient population, and ezetimibe or placebo comparator groups. Patients could receive intensive statin therapy but not in the statin intolerance and monotherapy studies. The effects of evolocumab on percent change from baseline for non-HDL-C, ApoB, and lipoprotein(a) and achievement of treatment goals for non-HDL-C and ApoB were examined. Compared with placebo, evolocumab at both approved dosing regimens substantially reduced mean non-HDL-C (Q2W dose: -49% to -56%, monthly dose: -48% to -52%), mean ApoB (Q2W dose: -46% to -52%, monthly dose: -40% to -48%), and median lipoprotein(a) (Q2W dose: -22% to -38%, monthly dose: -20% to -33%) at 12 weeks. Effects on all 3 parameters persisted over 5 years. Lipid-lowering effects were consistent among the patient populations examined (hypercholesterolemia/mixed dyslipidemia, statin intolerance, heterozygous familial hypercholesterolemia, and type 2 diabetes mellitus). Conclusions In this pooled analysis, evolocumab substantially reduced non-HDL-C, ApoB, and lipoprotein(a) compared with placebo. The effect was consistent and maintained in various patient populations over 5 years.

A Phase 1, Randomized, Double-Blind, Single-Dose, Placebo-Controlled Safety, Tolerability, And Pharmacokinetic/Pharmacodynamic Study Of Evolocumab In Healthy Chinese Subjects.

PURPOSE: Evolocumab is a human monoclonal antibody that reduces circulating low-density lipoprotein cholesterol (LDL-C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Data on evolocumab pharmacokinetics and pharmacodynamics are derived mostly from Caucasian populations. The objectives of this study were to characterize the single-dose pharmacokinetic and pharmacodynamic parameters, safety, and tolerability of evolocumab in healthy Chinese subjects. SUBJECTS AND METHODS: This was a phase 1, randomized, double-blind, placebo-controlled study (CTR20150465). Two parallel cohorts were randomized 5:1 to receive single subcutaneous injections of either evolocumab (140 mg or 420 mg) or placebo. Pharmacokinetics, pharmacodynamics, and safety were evaluated through day 85. The primary endpoints were maximum concentration (Cmax) and area under the drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast). RESULTS: Thirty-six men (median age 26) were enrolled to receive evolocumab 140 mg (n=15), evolocumab 420 mg (n=15), or placebo (n=6). After 140 mg and 420 mg evolocumab, mean (SD) Cmax was 13.8 (3.6 µg/mL and 67.6 (15.2) µg/mL, respectively, and mean (SD) AUClast was 166 (55) day·µg/mL and 1110 (274) day·µg/mL, respectively. LDL-C declined reversibly, with reductions of 70% at 140 mg and 71% at 420 mg. Maximum effects on LDL-C and PCSK9 levels were reached by day 15 and 24 hrs, respectively, at 140 mg, and by day 22 and 4 hrs, respectively, at 420 mg. No serious adverse events occurred and the overall incidence of treatment-emergent adverse events was similar for evolocumab and placebo: 26.7% (140 mg) and 33.3% (placebo); 66.7% (420 mg) and 66.7% (placebo). CONCLUSION: In this population of healthy Chinese subjects, single 140 mg and 420 mg doses of evolocumab exhibited nonlinear kinetics and more than dose-proportional increases in exposure, were associated with up to 71% reduction in LDL-C, and demonstrated a safety profile similar to placebo.

Efficacy and safety of evolocumab in individuals with type 2 diabetes mellitus: primary results of the randomised controlled BANTING study.

AIMS/HYPOTHESIS: The study aimed to examine the efficacy of 12 weeks of monthly evolocumab or placebo in lowering LDL-cholesterol (LDL-C) in individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia and on a maximum-tolerated statin of at least moderate intensity. METHODS: For this randomised, placebo-controlled outpatient study, eligible individuals were ≥18 years old with type 2 diabetes, HbA1c <10% (86 mmol/mol), had been on stable pharmacological therapy for diabetes for ≥6 months and were taking a maximum-tolerated statin dose of at least moderate intensity. Lipid eligibility criteria varied by history of clinical cardiovascular disease. Participants were randomised 2:1 to evolocumab 420 mg s.c. or placebo. Randomisation was performed centrally via an interactive web-based or voice recognition system. Allocation was concealed using the centralised randomisation process. Treatment assignment was blinded to the sponsor study team, investigators, site staff and patients throughout the study. Co-primary endpoints were mean percentage change in LDL-C from baseline to week 12 and to the mean of weeks 10 and 12. Additional endpoints included LDL-C <1.81 mmol/l, LDL-C reduction ≥50% and other lipids. Exploratory analyses included percentage changes in fasting and post mixed-meal tolerance test (MMTT) lipoproteins and lipids, glucose metabolism variables and inflammatory biomarkers. RESULTS: In total, 421 individuals were randomised and analysed, having received evolocumab (280 participants) or placebo (141 participants) (mean [SD] age 62 [8] years; 44% women; 77% white). Evolocumab decreased LDL-C by 54.3% (1.4%) at week 12 (vs 1.1% [1.9%] decrease with placebo; p < 0.0001) and by 65.0% (1.3%) at the mean of weeks 10 and 12 (vs 0.8% [1.8%] decrease with placebo; p < 0.0001); it also decreased non-HDL-cholesterol (HDL-C) by 46.9% (1.3%) at week 12 (vs 0.6% [1.8%] decrease with placebo) and by 56.6% (1.2%) at the mean of weeks 10 and 12 (vs 0.1% [1.6%] decrease with placebo). Evolocumab significantly improved levels of other lipids and allowed more participants to reach LDL-C <1.81 mmol/l or a reduction in LDL-C levels ≥50%. After an MMTT (120 min), there were favourable changes (p < 0.05; nominal, post hoc, no multiplicity adjustment) in chylomicron triacylglycerol (triglycerides), chylomicron cholesterol, VLDL-C and LDL-C. Evolocumab had no effect on glycaemic variables and was well tolerated. CONCLUSIONS/INTERPRETATION: In statin-treated individuals with type 2 diabetes and hypercholesterolaemia or mixed dyslipidaemia, evolocumab significantly reduced LDL-C and non-HDL-C. Favourable changes (p < 0.05) were observed in postprandial levels of chylomicrons, VLDL-C and LDL-C. TRIAL REGISTRATION: ClinicalTrials.gov NCT02739984 FUNDING: This study was funded by Amgen Inc. DATA AVAILABILITY: Qualified researchers may request data from Amgen clinical studies. Complete details are available at www.amgen.com/datasharing .

Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Primary results of the BERSON clinical trial.

AIM: To evaluate the lipid-lowering efficacy and safety of evolocumab combined with background atorvastatin in patients with type 2 diabetes mellitus (T2DM) and hyperlipidaemia or mixed dyslipidaemia. MATERIALS AND METHODS: BERSON was a double-blind, 12-week, phase 3 study (NCT02662569) conducted in 10 countries. Patients ≥18 to ≤80 years with type T2DM received atorvastatin 20 mg/d and were randomised 2:2:1:1 to evolocumab 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) or placebo Q2W or QM. Co-primary endpoints were the percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to week 12 and from baseline to the mean of weeks 10 and 12. Additional endpoints included atherogenic lipids, glycaemic measures, and adverse events (AEs). RESULTS: Overall, 981 patients were randomised and received ≥1 dose of study drug. Evolocumab significantly reduced LDL-C versus placebo at week 12 (Q2W, -71.8%; QM, -74.9%) and at the mean of weeks 10 and 12 (Q2W, -70.3%; QM, -70.0%; adjusted P < 0.0001 for all) when administered with atorvastatin. Non-high-density lipoprotein cholesterol, apolipoprotein B100, total cholesterol, lipoprotein (a), triglycerides, high-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol improved significantly with evolocumab versus placebo. The overall incidence of AEs was similar between evolocumab and placebo-treated patients, and there were no clinically meaningful differences in changes over time in glycaemic variables (fasting serum glucose and HbA1c) between the two groups. CONCLUSIONS: In patients with T2DM and hyperlipidaemia or mixed dyslipidaemia on statin, evolocumab significantly reduced LDL-C and other atherogenic lipids, was well tolerated, and had no notable impact on glycaemic measures.

Randomized study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Pre-specified analysis of the Chinese population from the BERSON clinical trial.

AIM: The aim of this study was to evaluate the efficacy and safety of evolocumab with background atorvastatin in Chinese patients with type 2 diabetes mellitus (T2DM) and hyperlipidaemia or mixed dyslipidaemia. MATERIALS AND METHODS: This is a pre-specified analysis of patients in the BERSON study (ClinicalTrials.gov, NCT02662569) in China. Patients initiated background atorvastatin 20 mg/d, after which they were randomized 2:2:1:1 to evolocumab 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) or to placebo Q2W or QM. Co-primary endpoints were percentage change in LDL cholesterol (LDL-C) from baseline to week 12 and from baseline to the mean of weeks 10 and 12. Additional endpoints included atherogenic lipids, glycaemic measures and adverse events (AEs). RESULTS: Among 453 patients randomized in China, 451 received at least one dose of study drug (evolocumab or placebo). Evolocumab significantly reduced LDL-C compared with placebo at week 12 (Q2W, -85.0%; QM, -74.8%) and at the mean of weeks 10 and 12 (Q2W, -80.4%; QM, -81.0%) (adjusted P < 0.0001 for all) when administered with background atorvastatin. Non-HDL-C, ApoB100, total cholesterol, Lp(a), triglycerides, HDL-C and VLDL-C significantly improved with evolocumab vs placebo. No new safety findings were observed with evolocumab. The incidence of diabetes AEs was higher with evolocumab compared with placebo. There were no differences over time between evolocumab and placebo in measures of glycaemic control. CONCLUSIONS: In patients in China with T2DM and hyperlipidaemia or mixed dyslipidaemia receiving background atorvastatin, evolocumab significantly reduced LDL-C and other atherogenic lipids, was well tolerated, and had no notable impact on glycaemic measures.

Rationale and design of a randomized study to assess the efficacy and safety of evolocumab in patients with diabetes and dyslipidemia: The BERSON clinical trial.

Type 2 diabetes mellitus (T2DM) is a major independent risk factor for cardiovascular disease, and diabetic dyslipidemia is a major contributor to cardiovascular risk in these patients. Here we report the rationale and design of a phase 3, double-blind study specifically designed to evaluate the lipid-lowering efficacy of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab in patients with T2DM and hyperlipidemia or mixed dyslipidemia who are on background statin therapy. In the BERSON (evolocumaB Efficacy for LDL-C Reduction in subjectS with T2DM On background statiN) trial, patients with T2DM, a screening low-density lipoprotein cholesterol (LDL-C) level of ≥ 2.6 mmol/L (≥100 mg/dL) or ≥ 3.4 mmol/L (≥130 mg/dL), and with or without statin treatment at screening, respectively, were enrolled and started on atorvastatin 20 mg/day for a lipid stabilization period of at least 4 weeks. Then, patients were randomly assigned in a 2:2:1:1 ratio to receive atorvastatin 20 mg once daily plus either evolocumab 140 mg every 2 weeks (Q2W), evolocumab 420 mg every month (QM), placebo Q2W, or placebo QM. The co-primary outcome measures were the percentage change from baseline in LDL-C at week 12 and the percentage change from baseline in LDL-C at the mean of weeks 10 and 12. The BERSON trial has completed enrollment. The study completed in the first half of 2018, and will provide information on the efficacy and safety of evolocumab in patients with T2DM and dyslipidemia.

Effect of Evolocumab on Lipoprotein Particles.

The level of low-density lipoprotein cholesterol (LDL-C) reflects the cholesterol carried mainly by low-density lipoprotein particles (LDL-P). LDL-C, however, does not always correlate with LDL-P because of the variable amounts of cholesterol per particle. Consideration of LDL-P concentrations in addition to LDL-C may help guide therapeutic decisions in a select number of patients. Evolocumab is a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9 that lowers both LDL-C and cardiovascular events. To evaluate the effect of evolocumab on serum levels and size of lipoprotein particles, we conducted a post hoc subanalysis of 619 patients from the Durable Effect of PCSK9 Antibody Compared with Placebo Study or DESCARTES trial, a 52-week, randomized, double-blind, placebo-controlled, global study of patients with hyperlipidemia. At baseline, mean LDL-P concentration was 1077 nmol/L for the placebo group and 1100 nmol/L for the evolocumab group. In patients receiving evolocumab, week 52 total LDL-P concentration decreased to 610 nmol/L, a treatment difference of 50% versus placebo. Evolocumab also reduced concentrations of medium very low-density lipoprotein particles (VLDL-P), small VLDL-P, and intermediate-density lipoprotein particle: median (Q1, Q3) changes were -15.2% (-48, 48), -29% (-54, 18), and -36% (-70, 22), respectively. Mean (95% confidence interval) % changes in total LDL particle size in the evolocumab group was -1.7 (-2.0, -1.4); % changes in HDL and VLDL particle sizes were 1.1 (0.7, 1.5) and 8.7 (7.0, 10.5), respectively. Changes in total LDL, HDL, and VLDL particle sizes (vs placebo) were all significant (p <0.001). In conclusion, evolocumab significantly lowers atherogenic lipoprotein particles including low-density and remnant lipoproteins.

Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome.

AIM: To examine the lipid and glycaemic effects of 52 weeks of treatment with evolocumab. MATERIALS AND METHODS: The Durable Effect of PCSK9 Antibody Compared with Placebo Study (DESCARTES) was a 52-week placebo-controlled trial of evolocumab that randomized 905 patients from 88 study centres in 9 countries, with 901 receiving at least one dose of study drug. For this post-hoc analysis, DESCARTES patients were categorized by baseline glycaemic status: type 2 diabetes, impaired fasting glucose (IFG), metabolic syndrome (MetS) or none of these. Monthly subcutaneous evolocumab (420 mg) or placebo was administered. The main outcomes measured were percentage change in LDL-cholesterol (LDL-C) at week 52 and safety. RESULTS: A total of 413 patients had dysglycaemia (120, type 2 diabetes; 293, IFG), 289 had MetS (194 also had IFG) and 393 had none of these conditions. At week 52, evolocumab reduced LDL-C by >50% in all subgroups, with favourable effects on other lipids. No significant differences in fasting plasma glucose, HbA1c, insulin, C-peptide or HOMA indices were seen in any subgroup between evolocumab and placebo at week 52. The overall incidence of new-onset diabetes mellitus did not differ between placebo (6.6%) and evolocumab (5.6%); in those with baseline normoglycaemia, the incidences were 1.9% and 2.7%, respectively. Incidences of AEs were similar in evolocumab- and placebo-treated patients. CONCLUSIONS: Evolocumab showed encouraging safety and efficacy at 52 weeks in patients with or without dysglycaemia or MetS. Changes in glycaemic parameters did not differ between evolocumab- and placebo-treated patients within the glycaemic subgroups examined.

Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial.

BACKGROUND: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil. METHODS: In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512. FINDINGS: From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p<0·0001), stroke volume 3·6 mL (0·5-6·7, p=0·0217), left ventricular end-systolic diameter -1·8 mm (-2·9 to -0·6, p=0·0027), left ventricular end-diastolic diameter -1·3 mm, (-2·3 to 0·3, p=0·0128), heart rate -3·0 beats per min (-5·1 to -0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p=0·0069). The frequency of adverse clinical events did not differ between groups. INTERPRETATION: Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. FUNDING: Amgen.

Relative bioavailability, food effect, and safety of the single-dose pharmacokinetics of omecamtiv mecarbil following administration of different modified-release formulations in healthy subjects.

OBJECTIVE: Omecamtiv mecarbil is a novel small molecule that directly activates cardiac myosin and increases cardiac contractility without increasing cardiac myocyte intracellular calcium. This study evaluated the relative bioavailability, food effect, and safety of several modified-release (MR) formulations of omecamtiv mecarbil. METHODS: This was a phase 1, randomized, open-label, 4-way crossover, incomplete block-design study evaluating 5 MR formulations of omecamtiv mecarbil vs. an immediate-release (IR) formulation. MATERIALS: Healthy subjects were randomized to 1 of 30 possible sequences: within each sequence, subjects were assigned to receive a single 25-mg dose of 2 of the 6 possible formulations in the fasting and/or fed states. RESULTS: 65 subjects were screened and enrolled; 5 were replacement subjects. Pharmacokinetic and safety data were analyzed from 62 and 63 subjects in the fasting and fed states, respectively. Compared with the IR formulation, median t(max) was longer (0.5 vs. 2 - 10 hours), and mean C(max) was lower for all 5 MR formulations (262 vs. 34 - 78 ng/mL); t(1/2,z) was similar (18 - 21 hours). The relative bioavailability was high (> 75%) for three MR formulations but lower (< 65%) for the other two. Overall, the effect of food on omecamtiv mecarbil pharmacokinetics was minimal for four of the MR formulations. The pharmacokinetics of the inactive metabolites M3 and M4 were similar across all formulations. CONCLUSIONS: The relative bioavailability of omecamtiv mecarbil was high (> 75%) for 3 of the five MR formulations. Food had a marginal, nonclinically meaningful effect on the pharmacokinetics of the MR formulations of omecamtiv mecarbil.

Effects of Evolocumab on Vitamin E and Steroid Hormone Levels: Results From the 52-Week, Phase 3, Double-Blind, Randomized, Placebo-Controlled DESCARTES Study.

RATIONALE: Vitamin E transport and steroidogenesis are closely associated with low-density lipoproteins (LDLs) metabolism, and evolocumab can lower LDL cholesterol (LDL-C) to low levels. OBJECTIVE: To determine the effects of evolocumab on vitamin E and steroid hormone levels. METHODS AND RESULTS: After titration of background lipid-lowering therapy per cardiovascular risk, 901 patients with an LDL-C ≥2.0 mmol/L were randomized to 52 weeks of monthly, subcutaneous evolocumab, or placebo. Vitamin E, cortisol, adrenocorticotropic hormone, and gonadal hormones were analyzed at baseline and week 52. In a substudy (n=100), vitamin E levels were also measured in serum, LDL, high-density lipoprotein, and red blood cell membranes at baseline and week 52. Absolute vitamin E decreased in evolocumab-treated patients from baseline to week 52 by 16% but increased by 19% when normalized for cholesterol. In the substudy, vitamin E level changes from baseline to week 52 mirrored the changes in the lipid fraction, and red blood cell membrane vitamin E levels did not change. Cortisol in evolocumab-treated patients increased slightly from baseline to week 52, but adrenocorticotropic hormone and the cortisol:adrenocorticotropic hormone ratio did not change. No patient had a cortisol:adrenocorticotropic hormone ratio <3.0 (nmol/pmol). Among evolocumab-treated patients, gonadal hormones did not change from baseline to week 52. Vitamin E and steroid changes were consistent across subgroups by minimum postbaseline LDL-C <0.4 and <0.6 mmol/L. CONCLUSIONS: As expected, vitamin E levels changed similarly to lipids among patients treated for 52 weeks with evolocumab. No adverse effects were observed in steroid or gonadal hormones, even at very low LDL-C levels. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01516879.