Table I.
Clinical trials concerning evolocumab (AMG 145) – PROFICIO Program
| Phase II | |||||
|---|---|---|---|---|---|
| Study | Population | Dosage | LDL-C reduction | ||
| MENDEL (n = 406, evolocumab = 271, ezetimibe = 45, placebo = 90) [59] | Patients with hypercholesterolemia (LDL-C in the range 100–190 mg/dl) without lipid-lowering therapy | Evolocumab 70, 105, or 140 mg every 2 weeks, 280, 350, or 420 mg every 4 weeks, ezetimibe 10 mg only; time of treatment = 12 weeks |
37–53% (vs. placebo) | ||
| RUTHERFORD (n = 168, evolocumab = 112, placebo = 56) [60] | Patients with heterozygous FH and hypercholesterolemia (LDL-C ≥ 100 mg/dl) during statin treatment with or without ezetimibe | Evolocumab 350 or 420 mg every 4 weeks; time of treatment = 12 weeks |
44–56% (vs. placebo) | ||
| LAPLACE-TIMI 57 (n = 631, evolocumab = 474, placebo = 157) [61] | Patients with hypercholesterolemia (LDL-C ≥ 85 mg/dl) during statin treatment with or without ezetimibe | Evolocumab 70, 105, or 140 mg every 2 weeks, 280, 350, or 420 mg every 4 weeks; time of treatment = 12 weeks |
42–66% (vs. placebo) | ||
| GAUSS (n = 160, placebo = 33, evolocumab = 127) [62] | Patients with history of statin intolerance | Evolocumab 280, 350, or 420 mg every 4 weeks, 420 mg + ezetimibe 10 mg daily every 4 weeks, ezetimibe 10 mg only; time of treatment = 12 weeks |
26–47% (vs. placebo) | ||
| YUKAWA (n = 310, evolocumab = 207, placebo = 103) [70] | Patients at high risk for cardiovascular events with hypercholesterolemia (LDL-C ≥ 116 mg/dl) during statin treatment | evolocumab 70 or 140 mg every 2 weeks, 280 or 420 mg every 4 weeks; time of treatment = 12 weeks |
53–69% (vs. placebo) | ||
| Phase III | |||||
| Study | Population | Dosage | LDL-C reduction | Percentage of patients achieving LDL-C level < 70 mg/dl | Additional results |
| MENDEL 2 (n = 614) [71] | Patients with hypercholesterolemia (LDL-C in the range 100–190 mg/dl) and Framingham risk scores ≤ 10% | Evolocumab 140 mg every 2 weeks, 420 mg every 4 weeks, ezetimibe 10 mg daily, placebo; time of treatment = 12 weeks |
55–57% in evolocumab group compared with placebo and 38–40% compared with ezetimibe | 69–72% vs. 0–1% vs. 1–2% (evolocumab vs. placebo vs. ezetimibe) | Significant reduction of APOB, Lp(a), non-HDL-C, TG, VLDL as well as TC/HDL-C and APOB/APOA1; significant increase in HDL-C compared with placebo |
| RUTHERFORD-2 (n = 331) [72] | Patients with heterozygous FH and hypercholesterolemia (LDL-C ≥ 100 mg/dl) despite intense lipid-lowering therapy | Evolocumab 140 mg every 2 weeks, 420 mg every 4 weeks, placebo; time of treatment = 12 weeks |
60–66% in evolocumab group compared with placebo | 63–68% vs. 2% (evolocumab vs. placebo) | Reduction of TG by 19.6% and Lp(a) by 31.6%; increase of HDL-C by 9.2% compared with placebo |
| LAPLACE-2 (n = 1899) [73] | Patients with hypercholesterolemia (LDL-C ≥ 150 mg/dl (no statin at screening), ≥ 100 mg/dl (non-intensive statin), or ≥ 80 mg/dl (intensive statin)). Intensive statin therapy was defined as daily atorvastatin (≥ 40 mg), rosuvastatin (20 mg), simvastatin (80 mg), or any statin plus ezetimibe |
Evolocumab 140 mg every 2 weeks, 420 mg every 4 weeks, ezetimibe 10 mg daily, placebo; time of treatment = 12 weeks |
59–66% in evolocumab group from baseline and 63–75% compared with placebo | 86–94% of patients in moderate-intensity statin therapy with evolocumab, 93–95% of patients in high-intensity statin therapy with evolocumab, 17–20% of patients receiving moderate-intensity statins and 51–62% of those receiving high-intensity statins with ezetimibe | Significant reduction of non-HDL-C (52–59% from baseline, 58–65% vs. placebo), APOB (47–56% from baseline, 51–59% vs. placebo) and Lp(a) (24–39% from baseline, 21–36% vs. placebo) for all statin groups; reduction in TG (6–16% from baseline, 12–30% vs. placebo); increase in HDL-C (5–10% from baseline, 4–10% vs. placebo) |
| GAUSS-2 (n = 307) [74] | Patients with hypercholesterolemia and statin intolerance (LDL-C ≥ 100 mg/dl with diagnosed CHD or risk equivalent, ≥ 130 mg/dl without CHD or risk equivalent and ≥ 2 risk factors, ≥ 160 mg/dl without CHD or risk equivalent and one risk factor, or ≥ 190 mg/dl without CHD or risk equivalent and no risk factors) |
Evolocumab 140 mg every 2 weeks, 420 mg every 4 weeks, ezetimibe 10 mg daily; time of treatment = 12 weeks |
55–56% from baseline, 37–39% compared with ezetimibe | 87.5% vs. 2% (evolocumab vs. ezetimibe) | Reduction of Lp(a) by 22–27% vs. 1.7–5.8% (evolocumab vs. ezetimibe) |
| DESCARTES (n = 901) [75] | Patients with hypercholesterolemia (LDL-C ≥ 75 mg/dl after 4–12 weeks run-in period of lipid-lowering therapy (diet alone, diet plus atorvastatin 10 mg daily, atorvastatin 80 mg daily, or atorvastatin 80 mg plus ezetimibe 10 mg daily)) | Evolocumab 420 mg every 4 weeks, ezetimibe 10 mg daily, placebo; time of treatment = 52 weeks |
49–62% compared with placebo | 82.3% vs. 6.4% (evolocumab vs. placebo) | Significant reduction of APOB (44.2%), non-HDL-C (50.3%), Lp(a) (22.4%) and TG (11.5%); significant increase of HDL-C (5.4%) and ApoA1 (3.0%) |
| TESLA (n = 50) [76] | Patients with homozygous FH on lipid-lowering therapy for at least 4 weeks | Evolocumab 420 mg every 4 weeks, placebo; time of treatment = 12 weeks |
30.9% compared with placebo | ||
| YUKAWA-2 (n = 404) [77] | Patients with hypercholesterolemia (LDL-C ≥ 100 mg/dl) at high risk for cardiovascular events based on Japan Atherosclerosis Society criteria | Evolocumab 140 mg every 2 weeks, 420 mg every 4 weeks, placebo; time of treatment = 12 weeks |
67–76% compared with placebo | 96–98% in evolocumab group, 0–4% in placebo group receiving atorvastatin 5 mg/day, 20% in placebo group receiving atorvastatin 20 mg/day | Reduction of APOB (56–66%), HDL-C (10–17%), Lp(a) (40–53%) |
| Ongoing | |||||
| Study | Purpose | ||||
| GAUSS-3 | to assess the efficacy and safety of evolocumab in subjects with statin intolerance | ||||
| OSLER-2 | to assess the long-term safety, tolerability and efficacy of evolocumab in subjects with hyperlipidemia or mixed dyslipidemia | ||||
| TAUSSIG | to assess the long-term efficacy and safety of evolocumab in subjects with severe FH | ||||
| FOURIER | to evaluate the influence of LDL-C reduction with evolocumab used in addition to other lipid-lowering treatment on the risk of cardiovascular death, MI, hospitalization for unstable angina, stroke, or coronary revascularization in subjects with clinically evident CVD | ||||
| GLAGOV | to evaluate the influence of LDL-C reduction with evolocumab on atherosclerotic plaque regression measured by intravascular ultrasound in subjects with CHD taking lipid-lowering therapy | ||||
| EBBINGHAUS | to evaluate the influence of treatment with evolocumab on neurocognitive functions in high cardiovascular risk subjects | ||||
| FLOREY | to evaluate the effect of evolocumab, atorvastatin, and combination therapy on lipoprotein kinetics (completed) | ||||
APOA1 – apolipoprotein A1, APOB – apolipoprotein B, CHD – coronary heart disease, CVD – cardiovascular disease, FH – familial hypercholesterolemia, HDL-C – high-density lipoprotein cholesterol, LDL-C – low-density lipoprotein cholesterol, Lp(a) – lipoprotein (a), MI – myocardial infarctions, TC – total cholesterol, TG – triglycerides.