Development of proprotein convertase subtilisin/kexin type 9 inhibitors and the clinical potential of monoclonal antibodies in the management of lipid disorders

Figures & data

Table 1 Standard doses of monoclonal antibodies

Drug	Once in 2 weeks (mg)	Once in 4 weeks (mg)
Alirocumab	75–150	300
Evolocumab	140	420
Bococizumaba	75/150	300

Note:

a Dose may be reduced if LDLc is <25 mg/dL.

Abbreviation: LDLc, low-density lipoprotein cholesterol.

Table 2 Phase 2 trials

Trial/study	Reference	Patients	Duration of trial	PCSK9 inhibitor	Results: reduction in LDLc
LAPLACE-TIMI-56	Giugliano et al^Citation20	631 LDLc ≥100 mg/dL On statin	12 weeks	Evolocumab	41.8–66.1%
MENDEL-1	Koren et al^Citation21	406 LDLc 100–190 mg/dL	12 weeks	Evolocumab	43.0–50.9% (depending on dose of Evolocumab)
GAUSS	Sullivan et al^Citation22	160 Statin intolerance	12 weeks	Evolocumab	43–63%
TESLA-A	Stein et al^Citation23	HoFH 8	12 weeks	Evolocumab	LDL(R)-negative: no response (2)
		LDLc ≥130 mg/dL			LDL(R)-positive but defective (6)
		TG ≤400 mg/dL			19–26%
RUTHERFORD	Raal et al^Citation24	169 LDLc ≥100 mg/dL	12 weeks	Evolocumab	44–56%
ROTH	Roth et al^Citation25	92 LDLc >100 mg/dL On atorvastatin 80 mg/day	16 weeks	Alirocumab	73.5±3.5%
STEIN	Stein et al^Citation26	HeFH: 77 LDLc >100 mg/dL On statin ± ezetimibe	12 weeks	Alirocumab	31.4–67.9% (depending upon dose of Alirocumab)
McKENNEY	McKenney et al^Citation27	183 LDLc ≥100 mg/dL On statins	12 weeks	Alirocumab	43–72% (mean=57%)
BALLANTYNE	Ballantyne et al^Citation28	351 LDLc <80 mg/dL On statins	24 weeks	Bococizumab	28–53%

Abbreviations: PCSK9, proprotein convertase subtilisin/kexin type 9; LDLc, low-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; LDL(R), low-density lipoprotein receptor; TG, triglyceride; HeFH, heterozygous familial hypercholesterolemia.

Table 4 Phase 3 trials (with Alirocumab)

Trial/study	Reference	Patients	Duration of trial	Drug (SC)	Results: reduction in LDLc
ODYSSEY LONG TERM	Robinson et al^Citation36	2,341 Very high CV risk Included HeFH Maximally tolerated dose of statin	52 weeks	70–150 mg biweekly	61.3% at 52 weeks
ODYSSEY CHOICE II	Ongoing trial	200 Uncontrolled on nonstatin lipids-lowering drugs (HeFH and non-FH)	24 weeks	300 mg monthly	Ongoing trial
ODYSSEY COMBO II	Cannon et al^Citation37	720 On maximally tolerated statin High CV risk On ezetimibe	12 weeks	75–150 mg biweekly	30% (P<0.0001)
ODYSSEY FH	Kastelein et al^Citation38	249 HeFH	24 weeks	75–150 mg biweekly	49% (P<0.0001)
ODYSSEY ALTERNATIVE	Moriarty et al^Citation39	314 Statin intolerance On ezetimibe	12 weeks	75–150 mg biweekly	Ongoing trial
ODYSSEY MONO	Roth et al^Citation40	103 LDL 100–190 mg/dl No lipid-lowering drugs High CV risk	24 weeks	75 mg biweekly	32%

Abbreviations: SC, subcutaneous; LDLc, low-density lipoprotein cholesterol; CV, cardiovascular; HeFH, heterozygous familial hypercholesterolemia; FH, familial hypercholesterolemia; LDL, low-density lipoprotein.

Table 3 Phase 3 trials (with Evolocumab)

Trial/study	Reference	Patients	Duration of trial	Mode of administration of Evolocumab	Results: reduction in LDLc
MENDEL-2	Koren et al^Citation29	614	12 weeks	Biweekly or monthly	Compared with placebo: 52–57%
		LDL 100–190 mg/dL Framingham risk factor ≤10			Compared with ezetimibe 38–40% (P<0.001)
GAUSS-2	Stroes et al^Citation30	307 LDLc 193±59 mg/dL	12 weeks	Biweekly or monthly	Compared with placebo 53–56% Compared with ezetimibe 37–39% (P<0.001)
OSLER-2	Koren et al^Citation31	1,104	52 weeks	Monthly	52.3% (mean) (P<0.0001)
TESLA-B	Raal et al^Citation32	49 LDLc ≥130 mg/dL TG ≤400 mg/dL	12 weeks	Monthly	30.9% (P<0.0001)
LAPLACE-2	Robinson et al^Citation33	2,067 – divided into three groups based on LDLc levels: high statin, ≥80 mg/dL; moderate statin, ≥100 mg/dL; no statin, ≥150 mg/dL	12 weeks	Biweekly or monthly	High statin: 68.3–76% Moderate statin: 68.2–71.4% Ezetimibe: 38.2–47.2%
DESCARTES	Bloom et al^Citation34	901 LDLc ≥75 mg/dl	52 weeks	Monthly	57.5% (at 12 weeks)
RUHTERFORD-2	Raal et al^Citation35	331 (HeFH) LDLc ≥100 mg/dl	12 weeks	Biweekly or monthly	Biweekly: 59.2% Monthly: 61.3%

Abbreviations: LDLc, low-density lipoprotein cholesterol; LDL, low-density lipoprotein; TG, triglyceride; HeFH, heterozygous familial hypercholesterolemia.

Table 5 Long-term trials

Trial/study	Reference	Patients		Drug and doses	Mean LDLc reduction			Clinical events
ODYSSEY LONG TERM	Robinson et al^Citation36	Number	2,341	Alirocumab 75–150 mg biweekly	Group	Basal	After 48 weeks	Control	3.3%
		Alirocumab	1,553	Duration 78 weeks	Control	121.9 mg/dl	122.6 mg/dl	Alirocumab	1.7%
		Control	788		Alirocumab	122.7 mg/dl	57.9 mg/dl	Reduction	48.5%
					Reduction 52.8% (P<0.001)
COMBINED OSLER-1 and OSLER-2	Sabatine et al^Citation41	Number	4,465	Evolocumab 140 mg biweekly or 420 mg monthly	Group	Basal	After 11.1 months	Placebo	2.18%
		Evolocumab	2,976	Duration: 11.1 months	Control	121 mg/dl	120 mg/dl	Evolocumab	0.95%
		HeFH	247		Evolocumab	120 mg/dl	48 mg/dl	Reduction	56.4%
		Statin intolerance	254		Reduction 61% (P<0.01)
		Placebo	1,489

Abbreviations: LDLc, low-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia.

Table 6 Comparison of three meta-analyses on PCSK9 inhibitors

Study parameter	Navarese et al^Citation43	Zhang et al^Citation42	Lipinski et al^Citation44
Number of trials analyzed	24	25	17
Total number of patients	10,159	12,200	13,083
Lipid profile changes
LDLc ↓	47.5%	Evolocumab	57%
		54.6%
		Alirocumab
		52.6%
Total cholesterol ↓	31.5%	36.6%	36%
Triglyceride ↓	↓	15.7%	↓
Non-HDL ↓	↓	↓	↓
Lipoproteins ↓	26.4%	48%	46%
Rise in HDL	6.3%	7.6%	–
Clinical outcome
All-cause mortality	Reduced	Reduced	Reduced
CV mortality	↓	–	↓
CV events	↓	–	↓
Adverse effects of PCSK9 inhibitors
Severe leading to discontinuation of drug	–	1.6–1.9%	–
Local injection-site reaction and muscle related	1–4%	1.6–2.2%	1–3%
Neurocognitive effects	1–3%	1.9–3.0%	Increased

Note: “–” Indicates data not available.

Abbreviations: PCSK9, proprotein convertase subtilisin/kexin type 9; LDLc, low-density lipoprotein cholesterol; HDL, high-density lipoprotein; CV, cardiovascular.

Table 7 Ongoing cardiovascular outcome trials of PCSK9 inhibitors

Trial/study	Authority	Patients	Drug	Dose	End points	Follow-up	Results expected
FOURIER	Clin Trials/Govt/CT2/Show/NCTO 1764633 (2014)	N=27,500 Age 40–85 years High CV risk LDLc ≥70 mg/dl, non-HDL ≥100 mg/dl, TG ≤400 mg/dl Statin therapy	Evolocumab	140 mg biweekly or 420 mg monthly	% fall in LDLc CV death, nonfatal MI, stroke, hospitalization for unstable angina or revascularization	5 years	2017–2018
ODYSSEY OUTCOME	Clin Trials/Govt/CT2/Show/NCTO 1663402 (2014)	N=18,000 Maximally tolerated statin LDLc ≥70 mg/dl, non-HDL ≥100 mg/dl, Apo-B ≥80 mg/dl	Alirocumab	75–150 mg biweekly	As above	64 months	–
SPIRE-1	Clin Trials/Govt/CT2/show/NCT 01975376	N=17,000 High CV risk LDLc ≥70 mg/dl but <100 mg/dl Statin therapy	Bococizumab	150 mg biweekly	As above	60 months	–
SPIRE-2	Clin Trials/Govt/CT2/show/NCT 01975389	High CV risk LDL ≥100 mg/dl	Bococizumab	150 mg biweekly	As above	60 months	–

Abbreviations: PCSK9 proprotein convertase subtilisin/kexin type 9; LDLc, low-density lipoprotein cholesterol; CV, cardiovascular; MI, myocardial infarction; HDL, high-density lipoprotein; TG, triglyceride; Apo-B, apolipoprotein B; LDL, low-density lipoprotein.

GiuglianoRPDesaiNRKohliPLAPLACE-TIMI 57 InvestigatorsEfficacy, safety and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 studyLancet201238095982007201723141813

 PubMedGoogle Scholar

KorenMJScottRKimJBEfficacy, safety and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 studyLancet201238098581995200623141812

 PubMed Web of Science ®Google Scholar

SullivanDOlssonAGScottREffect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trialJAMA2012308232497250623128163

 PubMed Web of Science ®Google Scholar

SteinEAHonarpourNWassermanSMXuFScottRRaalFJEffect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemiaCirculation2013128192113212024014831

 PubMed Web of Science ®Google Scholar

RaalFScottRSomaratneRLow-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomised trialCirculation2012126202408241723129602

 PubMed Web of Science ®Google Scholar

RothEMMcKenneyJMHanotinCAssetGSteinEAAtorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemiaN Engl J Med201236720189190023113833

 PubMed Web of Science ®Google Scholar

SteinEAGipeDBergeronJEffect of a monoclonal antibody to PCSK9, alirocumab to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trialLancet20123809836293622633824

 PubMed Web of Science ®Google Scholar

McKenneyJMKorenMJKereiakesDJHanotinCFerrandACSteinEASafety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, alirocumab, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapyJ Am Coll Cardiol201259252344235322463922

 PubMed Web of Science ®Google Scholar

BallantyneCMNeutelJCroppAResults of Bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemiaAm J Cardiol201511591212122125784512

 PubMed Web of Science ®Google Scholar

RobinsonJGFarnierMKrempfMEfficacy and safety of alirocumab in reducing lipids and cardiovascular events (ODYSSEY LONG TERM Investigators)N Engl J Med2015372161489149925773378

 PubMed Web of Science ®Google Scholar

CannonCPCariouBBlomDODYSSEY COMBO II InvestigatorsEfficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomised controlled trialEur Heart J201536191186119425687353

 PubMed Web of Science ®Google Scholar

KasteleinJJRobinsonJGFarnierMEfficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studiesCardiovasc Drugs Ther201428328128924842558

 PubMed Web of Science ®Google Scholar

MoriartyPMJacobsonTABruckertEEfficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomised phase 3 trialJ Clin Lipidol20148655456125499937

 PubMed Web of Science ®Google Scholar

RothEMTaskinenMRGinsbergHNMonotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trialInt J Cardiol20141761556125037695

 PubMed Web of Science ®Google Scholar

KorenMJLundqvistPBologneseMMENDEL-2 InvestigatorsAnti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumabJ Am Coll Cardiol201463232531254024691094

 PubMed Web of Science ®Google Scholar

StroesEColquhounDSullivanDGAUSS-2 InvestigatorsAnti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumabJ Am Coll Cardiol201463232541254824694531

 PubMed Web of Science ®Google Scholar

KorenMJGiuglianoRPRaalFJOSLER InvestigatorsEfficacy and safety of longer-term administration of evolocumab in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation against LDL-C (OSLER) randomized trialCirculation2014129223424324255061

 PubMed Web of Science ®Google Scholar

RaalFJHonarpourNBlomDJTESLA InvestigatorsInhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolemia (TESLA Part B): a randomized, double-blind, placebo-controlled trialLancet2015385996534135025282520

 PubMed Web of Science ®Google Scholar

RobinsonJGNedergaardBSRogersWJLAPLACE-2 InvestigatorsEffect of evolocumab or ezetimibe added to moderate – or high-intensity statin therapy on LDLc lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trialJAMA2014311181870188224825642

 PubMed Web of Science ®Google Scholar

BloomDJHalaTBologneseMA 52-week placebo-controlled trial of evolocumab in hyperlipidemiaN Engl J Med2014370191809181924678979

 PubMed Web of Science ®Google Scholar

RaalFJSteinEADufourRRUTHERFORD-2 InvestigatorsPCSK9 inhibition with evolocumab (AMG145) in heterozygous familial hypercholesterolemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trialLancet2015385996533134025282519

 PubMed Web of Science ®Google Scholar

SabatineMSGiuglianoRPWiviottSDEfficacy and safety of Evolocumab in reducing lipids and cardiovascular events (Open-Label Study of Long-term Evaluation against LDL Cholesterol Investigators) (OSLER)N Engl J Med2015372161500150925773607

 PubMed Web of Science ®Google Scholar

NavareseEPKolodziejczakMSchulzeVEffects of proprotein convertase subtilsin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysisAnn Intern Med201516314149

 Web of Science ®Google Scholar

ZhangXLZhuQQZhuLSafety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trialsBMC Med20151312326099511

 PubMed Web of Science ®Google Scholar

LipinskiMJBenedettoUEscarcegaROThe impact of proprotein convertase subtilisin/kexin type 9 serine protease inhibitor on lipids levels and outcomes in patients with primary hypercholesterolemia: a network meta-analysisEur Heart J201637653654526578202

 PubMed Web of Science ®Google Scholar