PCSK9 inhibitors: A new era of lipid lowering therapy

Table 2 Summary of important phase III PROFICIO (Program to Reduce LDL-C and Cardiovascular Outcomes Following Inhibition of PCSK9 In Different Populations) trials with Evolocumab

Name of trial	Ref. Allocation and blinding	No. of patients	Inclusion criteria	Study arms (with dosing)	Primary end point	Results
LAPLACE-2 (NCT01763866)	Robinson et al[75]; Randomized double blinded trial	1896	Individuals with LDL > 150 mg/dL (not on statin); or LDL > 100 mg/dL (on non-intensive statin); or LDL ≥ 80 mg/dL (with intensive statin therapy)	Initially randomized to daily moderate or high intensity atorvastatin for 4 wk. Patients were again randomized to Evolocumab (sc) vs ezetimibe vs placebo	Percentage change in calculated LDL cholesterol level from baseline to week 12	Evolocumab q2w and qmonthly: 63% to 75% reduction in LDL vs placebo Ezetimibe 19% to 32% reduction in LDL vs placebo
YUKAWA-2 (NCT01953328)	Kiyosue et al[76]; Randomized double blinded	404	Japanese patients with LDL > 70 on stable dose statins for > 4 wk and high cardiovascular risk	Initially randomized to daily atorvastatin of 5 mg or 20 mg for 4 wk. They were further randomized to Evolocumab (sc) at q2 week and qmonthly vs placebo	Percent change in calculated LDL-C from baseline at week 12	-67.0% to -76% reduction with Evolocumab compared to placebo (P < 0.0001)
GAUSS-2 (NCT01763905)	Stroes et al[78]; Randomized double blinded	307	Patients with LDL not at goal according to their cardiovascular risk and not on statin or low dose statin due to history of statin intolerance (> 2 statins) with stable LLT > 4 wk	Evolovumab (SC) at q2 week and qmonthly dosing vs Placebo (SC) + Ezetimibe (10 mg/d) daily	Percent change in LDL-C from baseline at the mean of weeks 10 and 12 and at week 12 Change from baseline LDL at week 12	-55.3% to -56.1% for Evolocumab compared with -16.6% to -19.2% for ezetimibe (P < 0.0001) -103.6 to -105.4 (Evolocumab) vs -33 to -39 (mg/dL)
MENDEL-2 (NCT01763827	Koren et al[77]; Randomized double-blinded	614	NCEP ATP III Framingham risk score of < 10% Fasting LDL-C ≥ 100 mg/dL and < 190 mg/dL	Oral placebo to SC placebo; ezetimibe to SC placebo and oral placebo to SC Evolocumab at dosing regimens of 140 mg biweekly and 420 mg monthly	Percent change from baseline in LDL-C level averaged at weeks 10 and 12	Percent LDL change from baseline averaged at weeks 10 and 12 in the: Once per 2 wk arm: -56.9% (with Evolocumab) vs -17.5 (with ezetimibe) vs -0.4% (placebo) For monthly arm: -58.8% (with evolocumab) vs -19.1 (with ezetimibe) vs -1.4% (placebo)
					Percent change from baseline in LDL-C level at week 12	Percent LDL change from baseline averaged at weeks 12: Once per 2 wk arm: -57% (with Evolocumab) vs -17.8 (with ezetimibe) vs 0.1% (placebo) For monthly arm: -56.1% (with Evolocumab) vs -18.6 (with ezetimibe) vs -1.3% (placebo)
RUTHERFORD-2 (NCT01763918)	Raal et al[72]; Randomized double blinded	329	Patients with heterozygous familial hypercholesterolemia who are on stable LLT for 4 wk and LDL > 100 mg/dL	Evolocumab (SC) at 140 mg q2 weeks vs placebo SC q2w AND Evolocumab SC qmonthly vs Placebo (SC)	Percent change from baseline in LDL-C level averaged at weeks 10 and 12 Percent change from baseline in LDL-C level at week 12	Percent LDL change from baseline averaged at weeks 12 in the: Once per 2 wk arm: -61.2% (with Evolocumab) vs -1.1% (with placebo) For monthly arm: -63.3% (with evolocumab) vs 2.3% (with placebo) Percent LDL change from baseline averaged at weeks 10 and 12 in the: Once per 2 wk arm: -61.3% (with Evolocumab) vs -2% (with placebo) For monthly arm: -55.7% (with Evolocumab) vs 5.5% (with placebo)
TESLA (NCT01588496)	Raal et al[82]; Randomized double-blinded	50	Homozygous familial hypercholesterolemia, on stable lipid-regulating therapy for at least 4 wk, LDL cholesterol ≥ 130 mg/dL (3.4 mmol/L); Triglyceride ≤ 400 mg/dL (4.5 mmol/L); Body weight of ≥ 40 kg at screening, and not receiving lipoprotein apheresis	Evolocumab (SC) 420 mg every 4 wk vs placebo (SC)	Percentage change in ultracentrifugation LDL cholesterol from baseline at week 12 compared with placebo, analyzed by intention-to-treat Percent change from baseline in LDL-C at week 52	Evolocumab significantly reduced ultracentrifugation LDL cholesterol at 12 wk by 30.9% (95%CI: -43.9% to -18.0%; P < 0.0001) vs placebo
DESCARTES (NCT01516879)	Blom et al[80]; Randomized, double-blinded	901	Fasting LDL ≥ 75 mg/dL and meeting the following on background LLT: (1) < 100 mg/dL for subjects with diagnosed CHD or CHD risk equivalent; (2) < 130 mg/dL for subjects without diagnosed CHD or CHD risk equivalent; (3) on maximal background LLT defined as atorvastatin 80 mg PO QD and ezetimibe 10 mg PO QD Fasting triglycerides ≤ 400 mg/dL	Evolocumab (SC) 420 mg every 4 wk with diet alone vs placebo with diet Evolocumab (SC) 420 mg every 4 wk with diet + atorvastatin 10 mg/d vs placebo with diet and atorvastatin 10 mg/d Evolocumab (SC) 420 mg every 4 wk + atorvastatin 80 mg/d vs placebo + atorvastatin 80 mg/d Evolocumab (SC) 420 mg every 4 wk + atorvastatin 80 mg/d + ezetimibe 10 mg/d vs placebo + atorvastatin 80 mg/d + ezetimibe 10 mg/d		Addition of Evolocumab resulted in LDL reduction by: (1) 51% to 60% in diet alone group; (2) 59% to 64% in patients on 10 mg atorvastatin (3) 51% to 62% in patients on 80 mg atorvastatin (4) 43% to 54% in patients with atorvastatin 80 mg/d and ezetimibe 10 mg/d (P < 0.001 for all)

SC: Subcutaneous; LLT: Lipid lowering therapy; heFH: Heterozygous familial hypercholesterolemia; CHD: Coronary heart disease; HCL: Hypercholesterolemia; MACE: Major adverse Cardiovascular Events; MI: Myocardial infarction; UA: Unstable angina; HR: Hazards ratio; CI: Confidence interval.