PCSK9 inhibitors: A new era of lipid lowering therapy

Table 1 Summary of phase III ODYSSEY trials with Alirocumab

Name of trial	Ref. Allocation and blinding	No. of patients	Inclusion criteria	Study arms (with dosing)	Primary end point	Results
LONG TERM (NCT01507831)	Seidah et al[7]; Randomized double blinded trial	2341	Either 1 or 2 below and who aren’t adequately controlled with their LLT: (1) Patients with heFH with or without CHD or CHD risk equivalents OR (2) Patients with HCL with CHD or CHD risk equivalents	Alirocumab (SC) (n = 1553) vs Placebo (SC) (n = 788) both with background LLT	Percentage change in calculated LDL cholesterol level from baseline to week 24	-61.0% change with Alirocumab vs +0.8% change with placebo (CI: -64.3 to -59.4; P < 0.001)
FH I (NCT01623115)	Kastelein et al[66]; Randomized double blinded	486	Patients with heterozygous familial hypercholesterolemia who are not adequately controlled with their lipid-modifying therapy	Alirocumab (SC) vs Placebo (SC) both with background LLT	Percent change in calculated LDL-C at week 24	-48.8% for Alirocumab compared with 9.1% for placebo (P < 0.0001)
FH II (NCT01709500)	Kastelein et al[66]; Randomized double blinded	249	Patients with heFH who are not adequately controlled with their LLT	Alirocumab (SC) vs Placebo (SC) both with background LLT	Percent change in LDL-C to week 24	-48.7% for Alirocumab compared with 2.8% for placebo (P < 0.0001)
HIGH FH (NCT01617655)	Kastelein et al[67]; Randomized double blinded	107	Patients with heterozygous familial hypercholesterolemia who are not adequately controlled with their lipid-modifying therapy with LDL > 160	Alirocumab (SC) (n = 72) vs Placebo (SC) (n = 35) both with background LLT	Percent change in calculated LDL-C at week 24	Percent decrease from baseline was 45.7% vs 6.6%, difference 39.1, P < 0.0001 Absolute difference in values of LDL-C at 24 wk 107 mg/dL vs 182 mg/dL
COMBO I (NCT01644175)	Colhoun et al[60]; Randomized double blinded	316	Patients with hypercholesterolemia and estbl CHD or CHD risk equivalents; not controlled with a maximally tolerated LLT, both at stable dose for at least 4 to 6 wk prior to screening	Alirocumab (SC) (n = 205) vs Placebo (SC) (n = 106)	Percent change in calculated LDL-C at week 24	-48.2% with Alirocumab (CI: -52.0% to -44.4%) and -2.3% with placebo (CI: -7.6% to 3.1%) for Alirocumab and placebo, respectively, an estimated mean difference of -45.9% (CI: -52.5% to -39.3%) (P < 0.0001)
COMBO II (NCT01644188)	Moriarty et al[65]; Randomized double blind	720	Patients with hypercholesterolemia and established CHD or CHD risk equivalents who are not adequately controlled with a maximally tolerated daily dose of statin at stable dose for at least 4 wk prior to the screening visit	Alirocumab (SC) + placebo (for ezetimibe) orally + background statin therapy (n = 467) vs Placebo (SC) + ezetimibe orally + Background statin therapy (n = 240)	Percent change in calculated LDL-C at week 24	Reductions in LDL-C from baseline were 50.6% ± 1.4% for Alirocumab vs 20.7% ± 1.9% for ezetimibe (difference 29.8% ± 2.3%; P < 0.0001)
OPTIONS I (NCT01730053)	Robinson et al[63]; Randomized double-blinded	355	Patients with prior CV disease + LDL-C ≥ 70 mg/dL, or CV risk factors + LDL-C ≥ 100 mg/dL	Alirocumab with atorvastatin 20 mg vs Ezetimibe with atorvastatin 20 mg vs Atorvastatin 40 mg	Percent change in calculated LDL-C to week 24	Percent reduction from baseline 44.1% (Alirocumab) vs 20.5% (ezetimibe) vs 5.0% (atorvastatin 40); P < 0.0001
				Alirocumab with atorvastatin 40 mg vs ezetimibe with atorvastatin 40 mg vs atorvastatin 80 mg vs rosuvastatin 20 mg		Percent reduction from baseline 54% (Alirocumab) vs 22.6% (Ezetimibe) vs 4.8% (Atorvastatin 80) vs 21.4% (rosuvastatin 40); P < 0.0001
OPTIONS II	Robinson et al[63]; Randomized double-blinded	305	Patients with prior CV disease + LDL-C ≥ 70 mg/dL, or CV risk factors + LDL-C ≥ 100 mg/dL	Alirocumab with rosuvastatin 10 mg vs ezetimibe with rosuvastatin 10 vs rosuvastatin 20	Percent change in calculated LDL-C to wk 24	Percent reduction from baseline 50.6% (Alirocumab) vs 14.4% (ezetimibe) vs 16.3% (rosuvastatin 20); P < 0.0001
				Alirocumab with rosuvastatin 20 mg vs ezetimibe with rosuvastatin 20 vs Rosuvastatin 40		Percent reduction from baseline 36.3% (Alirocumab) vs 11.0% (Ezetimibe) vs 20.3% (rosuvastatin 40); P < 0.0001
ALTERNATIVE (NCT01709513)	Moriarty et al[65]; Randomized double-blinded	314	Primary heFH with moderate, high or very high CV risk and history of statin intolerance	Alirocumab + oral placebo vs ezetimibe (10 mg/d) + sc placebo vs atorvastatin (20 mg/d) + sc placebo	Percent change in calculated LDL-C to week 24 in intention to treat group	Percent reduction from baseline 45% (Alirocumab) vs 14.6% (Ezetimibe) with a mean difference of -30.4%; P < 0.0001
CHOICE I (NCT01926782)	Stroes et al[78]; Randomized, double-blinded	803	Patients not having adequate control of their hypercholesterolemia based on their individual level of CVD risk	Alirocumab at q4 week regimen vs Placebo	Percent change in LDL from baseline to week 24 for Alirocumab q4w vs placebo in patients with hypercholesterolemia at moderate, high, or very high CVD risk with concomitant statin therapy (n = 547) Percent change in LDL from baseline to week 24 for Alirocumab q4w vs placebo in patients with hypercholesterolemia not on concomitant statin therapy (n = 256)	LDL was reduced by 58.7% with Alirocumab in patients on maximally tolerated statins (P < 0.001)
CHOICE II (NCT02023879)	Stroes et al[78]; Randomized, double-blinded	231	Patients with primary hypercholesterolemia (heFH or non-FH) not adequately controlled with their non statin lipid modifying therapy or diet and statin intolerance	Alirocumab (SC) vs placebo (SC)	The percent change in LDL-C from baseline to week 24	Alirocumab reduced LDL-C by 56.4% (P < 0.0001) vs placebo
LONG TERM (NCT01507831)	Robinson et al[62]; Randomized, double-blinded	2341	Either A or B below and who are not adequately controlled with their LLT: (1) Patients with heFH with or without established CHD or CHD risk equivalents OR (2) Patients with hypercholesterolemia together with established CHD or CHD risk equivalents	Alirocumab (SC) 150 mg every 2 wk vs placebo (SC) every 2 wk	Percentage change in calculated LDL cholesterol level from baseline to week 24, analyzed with the use of an intention-to-treat approach	150 mg Alirocumab every 2 wk had a 62% reduction in LDL as opposed to a 1% increase in LDL with placebo at 24 wk

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.

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.