PCSK9 inhibition in the management of hyperlipidemia: focus on evolocumab

Figures & data

Figure 1 LDL Recycling, PCSK9 Function, and Effect of PCSK9 Inhibition

Notes: (A) LDLRs are found on the hepatocyte cell surface. Upon binding an LDL particle, the LDLR–LDL particle complex enters the hepatocyte in a clathrin-coated vesicle. Intracellularly, the LDL and LDLR dissociate. LDL is delivered to a lysosome and degraded, while the LDLR is recycled back to the hepatocyte cell surface. (B): PCSK9 interferes with the LDLR recycling by preventing the separation of the LDLR from LDL. PCSK9 binds to the cell-surface LDLR; upon LDL binding and internalization, the PCSK9-bound LDLR fails to separate from the LDL particle. As a result, the LDLR is delivered to the lysosome and degraded along with the LDL, thus bypassing the process of recycling to the hepatocyte cell surface. (C): Monoclonal antibodies directed against PCSK9 prevent its interaction with the LDLR.
Abbreviations: LDL, low-density lipoprotein; LDLRs, LDL receptors; PCSK9, proprotein convertase subtilisin/kexin type 9.

Table 1 Anti-PCSK9 monoclonal antibodies marketed or in Phase III development

Generic name	Brand name	Manufacturer	Marketing status	Approved dosing regimens
Evolocumab	Repatha	Amgen, Inc. (Thousand Oaks, CA, USA)	Marketed	140 mg SC Q2Wa 420 mg SC QMa,b
Alirocumab	Praluent	Sanofi-Aventis and Regeneron (Tarrytown, NY, USA)	Marketed	75 mg SC Q2Wa 150 mg SC Q2Wa,c
Bococizumab	–	Pfizer, Inc. (New York, NY, USA)	Investigational (Phase III)	–

Notes:

a Primary hyperlipidemia with established clinical atherosclerotic cardiovascular disease or heterozygous familial hypercholesterolemia;

b homozygous familial hypercholesterolemia;

c if LDL-C response is inadequate with 75 mg SC Q2W.

Abbreviations: LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; Q2W, every 2 weeks; QM, monthly; SC, subcutaneously.

Table 2 Published PCSK9 monoclonal antibody Phase III trials

Antibody	Study name	N	Trial population and baseline fasting LDL-C	Background lipid therapy in all arms	Endpoint (weeks)	Antibody dosing regimen	LDL−C reduction vs controla	References
Evolocumab	LAPLACE-2	1,896	FH and NFH ≥3.9 mmol/L (≥150 mg/dL) – no statin ≥ 2.6 mmol/L (≥100 mg/dL) – nonintensive statin ≥2.1 mmol/L (≥80 mg/dL) – intensive statin	Statinsb	12	140 mg Q2W 420 mg QM	−68% to −76% vs PLA −40% to −47% vs EZE −55% to −70% vs PLA −39% to −41% vs EZE	Robinson et al^Citation47
	RUTHERFORD-2	329	HeFH ≥2.6 mmol/L (≥100 mg/dL)	Statin (±EZE)	12	140 mg Q2W 420 mg QM	−59% vs PLA −61% vs PLA	Raal et al^Citation46
	GAUSS-2	307	Intolerant to ≥2 statins FH and NFH ≥ NCEP ATP III LDL-C goal	Non-EZE LLTc	12	140 mg Q2W 420 mg QM	−38% vs EZE −38% vs EZE	Stroes et al^Citation48
	MENDEL-2	614	FH and NFH ≥2.6 mmol/L (≥100 mg/dL)	None	12	140 mg Q2W 420 mg QM	−57% vs PLA −39% vs EZE −55% vs PLA −38% vs EZE	Koren et al^Citation45
	DESCARTES	901	Various levels of CV risk FH and NFH ≥1.9 mmol/L (≥75 mg/dL)	Diet ± atorvastatin ± ezetimibed	52	420 mg QM	−48% to −62% vs PLA	Blom et al^Citation44
	TESLA Part B	49	HoFHe ≥3.4 mmol/L (≥130 mg/dL)	LLT, no apheresis	12	420 mg QM	−31% vs PLA	Raal et al^Citation64
Alirocumab	ODYSSEY COMBO I	316	High CV risk ≥1.8 mmol/L (≥70 mg/dL) – CVD ≥2.6 mmol/L (≥100 mg/dL) – CV risk factors	Statin ± other LLT	24	75–150 mg Q2Wf	−46% vs PLA	Kereiake et al^Citation52
	ODYSSEY COMBO II	720	High CV risk ≥1.8 mmol/L (≥70 mg/dL) – CVD ≥2.6 mmol/L (≥100 mg/dL) – no CVD	Statin	24	75–150 mg Q2Wf	−30% vs EZE	Cannon et al^Citation50
	ODYSSEY LONG TERM	2,341	HeFH, CVD, or high CV risk ≥1.8 mmol/L (≥70 mg/dL)	Statin ± other LLT	24	150 mg Q2W	−62% vs PLA	Robinson et al^Citation53
	ODYSSEY MONO	103	10-year risk of fatal CV events ≥1% and <5% ≥2.6 mmol/L (≥100 mg/dL) and <4.9 mmol/L (<190 mg/dL)	None	24	75–150 mg Q2Wf	−32% vs EZE	Roth et al^Citation54
	ODYSSEY ALTERNATIVE	314	Intolerant to ≥2 statins No muscle symptoms on single-blind placebo run-in FH and NFH ≥2.6 mmol/L (≥100 mg/dL) – moderate/high CV risk ≥1.8 mmol/L (≥70 mg/dL) – very high CV risk	No statins, EZE, red yeast rice, fibrates other than fenofibrate	24	75–150 mg Q2Wf	−30% vs EZE	Moriarty et al^Citation55
	ODYSSEY FH I	486	HeFH ≥1.8 mmol/L (≥70 mg/dL) – CVD ≥2.6 mmol/L (≥100 mg/dL) – no CVD	Statin ± other LLT	24	75–150 mg Q2Wf	−58% vs PLA	Kastelein et al^Citation51
	ODYSSEY FH II	249	HeFH ≥1.8 mmol/L (≥70 mg/dL) – CVD ≥2.6 mmol/L (≥100 mg/dL) – no CVD	Statin ± other LLT	24	75–150 mg Q2Wf	−51% vs PLA	Kastelein et al^Citation51
	ODYSSEY OPTION I	205	High CV risk ≥1.8 mmol/L (≥70 mg/dL) – CVD ≥2.6 mmol/L (≥100 mg/dL) – CV risk factors	Statin ± other non-EZE LLT	24	75–150 mg Q2Wf,g	−24% to −31% vs EZE −33% to −49% vs statin	Bays et al^Citation49

Notes:

a Least squares mean percent change from baseline vs control; control may include background statin or other lipid-lowering therapy as indicated in the “background lipid therapy in all arms” column.

b Patients randomized to one of five background statin doses: moderate intensity (atorvastatin 10 mg, simvastatin 40 mg, or rosuvastatin 5 mg daily) or high intensity (atorvastatin 80 mg or rosuvastatin 40 mg daily).

c Low-dose statin permitted: ≤70 mg atorvastatin; ≤140 mg simvastatin, pravastatin, lovastatin; ≤35 mg rosuvastatin; ≤280 mg fluvastatin.

d Patients assigned background LLT according to screening LDL-C and NCEP ATP III risk category: diet alone, diet plus atorvastatin 10 mg PO daily, diet plus atorvastatin 80 mg PO daily, or diet plus atorvastatin 80 mg PO daily and ezetimibe 10 mg PO daily.

e HoFH is a rare severe genetic disorder that most commonly results from mutations in both LDLR alleles. HoFH responds poorly to conventional cholesterol-lowering medications because of severe impairment in LDLR function.

f Starting dose of 75 mg Q2W with uptitration to 150 mg Q2W at week 12 if LDL ≥1.8 mmol/L (≥70 mg/dL).

g Randomization: alirocumab, ezetimibe 10 mg daily, or doubling of baseline atorvastatin dose (from 20 to 40 mg or from 40 to 80 mg or switch to rosuvastatin 40 mg daily).

Abbreviations: CV, cardiovascular; CVD, CV disease; DESCARTES, Durable Effect of PCSK9 Antibody Compared with Placebo Study; EZE, ezetimibe; FH, familial hypercholesterolemia; GAUSS-2, Goal Achievement after Utilizing an anti-PCSK9 antibody in Statin Intolerant Subjects Study 2; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LAPLACE-2, LDL-C Assessment with PCSK9 Monoclonal Antibody Inhibition Combined with Statin Therapy-2; LDL-C, low-density lipoprotein cholesterol; LDLR, LDL receptor; LLT, lipid-lowering therapy; MENDEL-2, Monoclonal Antibody against PCSK9 to Reduce Elevated LDL-C in Subjects Currently Not Receiving Drug Therapy for Easing Lipid Levels-2; NCEP ATP III, National Cholesterol Education Program Adult Treatment Panel III; NFH, nonfamilial hypercholesterolemia; PCSK9, proprotein convertase subtilisin/kexin type 9; PLA, placebo; PO, orally; Q2W, every 2 weeks; QM, monthly; RUTHERFORD-2, Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder; TESLA, Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities.

Table 3 Adverse events occurring in ≥3% of monoclonal antibody-treated patients and more frequently than with placebo

Adverse event	Placebo (%)	Monoclonal antibodya (%)
Evolocumab – 52-week trial	N=302	N=599
(DESCARTES)
Nasopharyngitis	9.6	10.5
Upper respiratory tract infection	6.3	9.3
Influenza	6.3	7.5
Back pain	5.6	6.2
Injection-site reactionsb	5.0	5.7
Cough	3.6	4.5
Urinary tract infection	3.6	4.5
Sinusitis	3.0	4.2
Headache	3.6	4.0
Myalgia	3.0	4.0
Dizziness	2.6	3.7
Musculoskeletal pain	3.0	3.3
Hypertension	2.3	3.2
Diarrhea	2.6	3.0
Gastroenteritis	2.0	3.0
Evolocumab – seven pooled	N=1,224	N=2,052
12-week placebo-controlled trials
Nasopharyngitis	3.9	4.0
Alirocumab – nine	N=1,276	N=2,476
placebo-controlled trialsc
Nasopharyngitis	11.1	11.3
Injection-site reactionsd	5.1	7.2
Influenza	4.6	5.7
Urinary tract infections	4.6	4.8
Diarrhea	4.4	4.7
Bronchitis	3.8	4.3
Myalgia	3.4	4.2
Muscle spasms	2.4	3.1
Sinusitis	2.7	3.0

Notes:

a Both indicated doses combined;

b erythema, pain, and bruising;

c median treatment duration, 65 weeks;

d erythema/redness, itching, swelling, pain/tenderness. Data from references 42 and 43.

Abbreviation: DESCARTES, Durable Effect of PCSK9 Antibody Compared with Placebo Study.

RobinsonJGNedergaardBSRogersWJEffect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trialJAMA2014311181870188224825642

 PubMed Web of Science ®Google Scholar

RaalFJSteinEADufourRPCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trialLancet2015385996533134025282519

 PubMed Web of Science ®Google Scholar

StroesEColquhounDSullivanDAnti-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

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

 PubMed Web of Science ®Google Scholar

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

 PubMed Web of Science ®Google Scholar

RaalFJHonarpourNBlomDJInhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA part B): a randomised, double-blind, placebo-controlled trialLancet2015385996534135025282520

 PubMed Web of Science ®Google Scholar

KereiakesDJRobinsonJGCannonCPEfficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I studyAm Heart J20151696906915e91326027630

 PubMed Web of Science ®Google Scholar

CannonCPCariouBBlomDEfficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trialEur Heart J201536191186119425687353

 PubMed Web of Science ®Google Scholar

RobinsonJGFarnierMKrempfMEfficacy and safety of alirocumab in reducing lipids and cardiovascular eventsN Engl J Med2015372161489149925773378

 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

MoriartyPMThompsonPDCannonCPEfficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trialJ Clin Lipidol20159675876926687696

 PubMed Web of Science ®Google Scholar

KasteleinJJGinsbergHNLangsletGODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemiaEur Heart J201536432996300326330422

 PubMed Web of Science ®Google Scholar

BaysHGaudetDWeissRAlirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trialJ Clin Endocrinol Metab201510083140314826030325

 PubMed Web of Science ®Google Scholar