Table 7 Efficacy and safety of evolocumab and alirocumab in different studies performed in the general population

Meta-analysis on Phase 2 or 3 randomized, controlled trials (RCTs) comparing treatment using PCSK9 antibodies with no anti-PCSK9 therapy in adults with hypercholesterolemia.

Twenty-four RCTs comprising 10,159 patients were included.

Treatment with PCSK9 antibodies led to marked reductions in LDL-C (mean difference, −47.49% [95% CI, −9.64% to −25.35%]; P < 0.001] and it reduced all-cause mortality ([OR], 0.45 [CI, 0.23 to 0.86]; P = 0.015; heterogeneity P = 0.63; I2 = 0%) and cardiovascular mortality (OR, 0.50 [CI, 0.23 to 1.10]; P = 0.084; heterogeneity P = 0.78; I2 = 0%).

The overall incidence of serious adverse events was 9.26% (573 of 6187) among patients treated with PCSK9 antibodies and 7.73% (307 of 3972) among patients who were not treated with PCSK9 antibodies (OR, 1.01 [CI, 0.87 to 1.18]; P = 0.879; heterogeneity P = 0.98; I2 = 0%).

Meta-analysis to evaluate the safety and efficacy of anti-PCSK9 antibodies in randomized, controlled trials (RCTs).

Twenty-five RCTs encompassing 12,200 patients were included

Evolocumab treatment significantly reduced LDL-C by −54.6% and by absolute −78.9 mg/dl versus placebo, and by −36.3% versus ezetimibe.

Alirocumab lowered LDL-C by −52.6% versus placebo, by −29.9% versus ezetimibe.

Alirocumab was associated with

an increased rate of injection-site reactions (RR: 1.48, 95% CI: 1.05 to 2.09, P = 0.02)

ODYSSEY FH I and II:

two randomized, double-blind studies to assess long-term alirocumab in patients with heterozygous familial hypercholesterolaemia

ODYSSEY FH I, n = 486; FH II, n = 249

subjects

Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; 257.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; 251.4% vs. placebo) in FH II (P, 0.0001).

Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo).

TESLA Part B:

randomised, double-blind, placebo-controlled phase 3 trial of subjects with homozygous familial hypercholesterolaemia, randomly allocated to receive subcutaneous evolocumab 420 mg or placebo every 4 weeks for 12 weeks.

50 eligible patients

Compared with placebo, evolocumab significantly reduced 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.

ODYSSEY LONG TERM:

randomized trial involving

subjects to receive

alirocumab (150 mg) or placebo for 78 weeks.

2341 patients at high risk for cardiovascular

events who had LDL cholesterol levels of 70 mg per deciliter or more and were receiving treatment with statins at the maximum tolerated

dose

At week 24, the difference between the alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was −62% (P < 0.001)

In a post hoc analysis, the rate of major adverse cardiovascular events was lower with alirocumab than with placebo (1.7% vs. 3.3%; hazard ratio, 0.52; 95% confidence interval, 0.31 to 0.90; nominal P = 0.02).

The alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%).

The GAUSS-2 trial:

12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg.

307 patients

At week 12, evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p < 0.001).

Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups.

OSLER Study:

two open-label, randomized trials of patients who had completed 1 of 12 phase 2 or 3 studies of evolocumab.

4465 eligible patients randomly assigned

to receive either evolocumab plus standard therapy or standard therapy alone.

As compared with standard therapy alone, evolocumab reduced the level of LDL-C by 61%, from a median of 120 mg per deciliter to 48 mg per deciliter (P < 0.001).

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% CI, 0.28 to 0.78; P = 0.003).

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

FOURIER study:

randomized, double-blind, placebo-controlled trial of patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter or higher who were receiving statin therapy.

The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization

27,564 patients were randomly assigned to receive evolocumab or matching placebo as subcutaneous injections

At 48 weeks, mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59% (P < 0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P < 0.001

No significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%).