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Table of Contents
DRUG THERAPY
Year : 2020  |  Volume : 21  |  Issue : 2  |  Page : 97-103  

PCSK9 monoclonal antibodies: An overview


1 Pharmacy Department, Heart Hospital, Hamad Medical Corporation, Doha, Qatar
2 Department of Cardiology, Al Khor Hospital, Hamad Medical Corporation, Doha, Qatar

Date of Submission19-Feb-2020
Date of Acceptance08-Mar-2020
Date of Web Publication29-Jun-2020

Correspondence Address:
Dr. Rasha Kaddoura
Heart Hospital, Hamad Medical Corporation, Doha
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/HEARTVIEWS.HEARTVIEWS_20_20

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   Abstract 


PCSK9 monoclonal antibodies are novel lipid-lowering therapy that have been extensively studied in patients with hypercholesterolemia either as monotherapy or as an add-on to other LLTs. PCSK9 monoclonal antibodies have significantly reduced the low-density lipoprotein cholesterol (LDL-C) plasma level resulting in a better LDL-C goal attainment. The commercially available PCSK9 monoclonal antibodies, alirocumab and evolocumab, have demonstrated reductions in major adverse cardiovascular events such as myocardial infarction, stroke, unstable angina, and the need for coronary revascularization but not mortality. PCSK9 monoclonal antibodies have demonstrated a favorable safety profile. The most reported side effects are mild injection site with no causal relationship proven between the inhibition of PCSK9 and neurocognitive or glycemic adverse events. In this overview, the efficacy and safety of PCSK9 monoclonal antibodies in the treatment of primary and familial hypercholesterolemia will be discussed.

Keywords: Alirocumab, antidrug antibody, bococizumab, cardiovascular diseases, evolocumab, familial hypercholesterolemia, neurocognitive, proprotein convertase subtilisin-kexin type 9 inhibitors


How to cite this article:
Kaddoura R, Orabi B, Salam AM. PCSK9 monoclonal antibodies: An overview. Heart Views 2020;21:97-103

How to cite this URL:
Kaddoura R, Orabi B, Salam AM. PCSK9 monoclonal antibodies: An overview. Heart Views [serial online] 2020 [cited 2020 Sep 24];21:97-103. Available from: http://www.heartviews.org/text.asp?2020/21/2/97/288322




   Introduction Top


The reduction in low-density lipoprotein cholesterol (LDL-C) using statin therapy has shown significant benefits in terms of the prevention of primary and secondary atherosclerotic cardiovascular diseases (ASCVDs).[1],[2] Patients on maximally-tolerated statin doses may still suffer from cardiovascular (CV) events,[2] inability to achieve target LDL-C, or intolerance to statin therapy. Subsequently, other lipid-lowering therapy (LLT) has been developed.[1] Although ezetimibe has resulted in additional LDL-C-lowering effect when added to statins, the improvement in CV outcomes was not impressive.[1],[3]

Monoclonal antibodies directed against proprotein convertase subtilisin/kexin type 9 (PCSK9) are an innovative LLT that has the ability to substantially reduce LDL-C levels.

Alirocumab and evolocumab are currently approved by the Food and Drug Administration (FDA) for heterozygous familial hypercholesterolemia (HeFH) and for the prevention of CV events in patients with established cardiovascular disease (CVD). Evidence of PCSK9 monoclonal antibodies in homozygous familial hypercholesterolemia (HoFH) is limited with only evolocumab being labeled for this indication.[4]

The American and the European guidelines[5],[6] have recently considered PCSK9 monoclonal antibody use in their recommendations. Although bococizumab development was stopped in 2016,[7] trials on other potential monoclonal antibodies are ongoing with encouraging initial results.[8],[9],[10],[11] The efficacy and the safety of PCSK9 monoclonal antibodies in the treatment of hypercholesterolemia will be discussed in this overview.


   Mechanism of Action Top


PCSK9 is a circulating plasma protein that is synthetized and secreted by hepatocytes.[12] It regulates the LDL receptor (LDLR) located on the surface of hepatocytes. LDLR is the receptor responsible for clearing the circulating LDL-C particles from plasma by endocytosis. By binding to LDLR, PCSK9 prevents the release of LDLR from the endocytosed vesicle and causes LDLR lysosomal destruction, thus preventing its recycling.[4] As a result, the LDLR density on the hepatocyte surfaces decreases affecting LDLR ability to eliminate LDL-C particles from the plasma, thus increasing their levels.[12] By inhibiting PCSK9 from binding to LDLR with the use of monoclonal antibodies, LDL-C degrades and the LDLRs can be recycled and accumulate on the hepatocyte surface accelerating LDL-C particle clearance from plasma, thus reducing their levels.[4]


   Hypercholesterolemia Top


The PCSK9 monoclonal antibodies were generally effective, safe and well-tolerated in early studies.[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26] The PCSK9 monoclonal antibodies have been extensively studied in Phase III clinical trials in primary and familial hypercholesterolemia. In general, evolocumab was studied in two dosing regimens 140 mg every 2 weeks (Q2W) and 420 mg monthly (QM), whereas alirocumab was administered as 75 mg Q2w (75Q2W) increased to 150 mg Q2W (150Q2W) at week 12 if LDL-D was ≥1.8 mmol/L (70 mg/dL) at week 8. Both monoclonal antibodies were administered subcutaneously either alone or on top of other LLTs over periods of time ranging from 12 weeks up to 104 week.[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44]

Primary hypercholesterolemia

Evolocumab in the LAPLACE-2[27] study (2014) reduced LDL-C by 59% to 66% (Q2W) or 62% to 65% (QM) at week 12 when added to moderate-intensity statins in patients with primary hypercholesterolemia and mixed dyslipidemia. LDL-C reductions by 86% to 90% (Q2W) and 93% to 95% (QM) were reported when added to high-intensity statins. LDL-C levels of <1.8 mmol/L (70 mg/dL) were achieved in about 86% to 94% of the patients on evolocumab as compared to 17% to 62% on ezetimibe. In the DESCARTES[38] trial (2014), a significant reduction of around 57% in LDL-C at week 12 and maintained through week 52 was observed with evolocumab (QM) when combined with diet alone or with atorvastatin 10 mg or 80 mg (in the absence or presence of ezetimibe).

The percentage of patients who achieved the LDL-C goal of < 1.8 mmol/L (70 mg/dL) was 82.3% with evolocumab versus 6.4% with placebo. In the diet-alone group, patients on evolocumab showed a least-square mean reduction in LDL-C of 55.7%. In the atorvastatin 10 mg group, atorvastatin 80 mg group, and atorvastatin 80 mg plus ezetimibe 10 mg group, the mean reductions in LDL-C were 61.6%, 56.8%, and 48.5%, respectively. All comparisons reached statistical significance.

Alirocumab when added to atorvastatin 20 mg and 40 mg in ODYSSEY OPTIONS I[45] trial (2015) significantly lowered LDL-C by 44.1% and 54.0% as compared to 20.5% and 22.6% with ezetimibe, respectively. In a third arm where atorvastatin 40 mg was switched to rosuvastatin 40 mg, the reduction of LDL-C was by 21.4%. In the arm of doubling atorvastatin dose, the reduction in LDL-C was only of an average of 5%. In ODYSSEY OPTIONS II[46] trial (2016), alirocumab when added to rosuvastatin 10 mg arm significantly reduced LDL-C by 50.6% compared to 14.4% of the patients on ezetimibe or 16.3% on double-dose rosuvastatin. When added to rosuvastatin 20 mg, alirocumab significantly decreased LDL-C by 36.3% compared to 11% with ezetimibe or to 15.9% with doubling the dose of rosuvastatin.

In both OPTIONS I and OPTIONS II trials, LDL-C reductions were observed at week 4 and maintained through the study duration, with an average of 80% of the patients on alirocumab achieving their LDL-C targets. ODESSEY COMBO I[37] trial (2015) showed an estimated mean difference in baseline LDL-C of − 45.9% (P < 0.0001) with alirocumab 75Q2W at week 24 which was maintained through week 52. The study enrolled patients with hypercholesterolemia at high CV risk and 75% of them achieved LDL-C target compared to 9% on placebo. A similar patient population was recruited in the ODESSEY COMBO II[44] trial (2015) over a similar duration. At week 24, LDL-C mean reduction with alirocumab versus ezetimibe was 50.6% versus 20.7% with a significant difference of −29.8%. Seventy seven percent of patients on alirocumab achieved LDL-C <1.8 mmol/L (70 mg/dL) versus 45.6% on ezetimibe.

In 2016, the ODYSSEY CHOICE I[40] and ODYSSEY CHOICE II[32] studies were published. Both studies recruited patients with hypercholesterolemia and at moderate-to-very high CV risk. At week 24 in ODYSSEY CHOICE I,[40] trial (2016), alirocumab 300 mg Q4W without statins showed a mean LDL-C change from baseline of −52.7% compared to + 0.3% with placebo. With statins, alirocumab showed a mean change of −58.8% compared to − 0.1% with placebo. The mean LDL-C change was significant in both the groups, and LDL-C reduction was maintained through week 48. In ODYSSEY CHOICE II[32] trial (2016), patients receiving fenofibrate or ezetimibe or diet alone were randomized to alirocumab 150 mg Q4W (150Q4W) or 75Q2W increased to 150Q2W at week 12 if LDL-C target was not achieved. The least-square mean LDL-C changes were − 51.7% and −53.5% versus placebo + 4.7% (P < 0.0001, for both) with 63.9% and 70.3% of the patients on alirocumab achieving their CV risk-specific LDL-C goal versus 1.8% on placebo, respectively.

Both monoclonal antibodies were studied as monotherapy. In the MENDEL-2[31] trial (2014), baseline LDL-C was significantly decreased by an average of 57% and 56.1% with biweekly and monthly evolocumab compared to 17.8% and 18.6% with ezetimibe or 0.1% and 1.3% with placebo, respectively. In the evolocumab groups, 69% of the patients achieved LDL-C <1.8 mmol/L (70 mg/dL) versus 1% in either the ezetimibe or placebo group. ODYSSEY MONO[47] study (2015) reported that alirocumab (75Q2W) led to a significant 47.2% reduction in LDL-C compared with 15.6% with ezetimibe. Furthermore, both agents were studied in specified patient populations, such as Japanese or diabetic patients.

In a Japanese[28] study (2016), evolocumab on top of atorvastatin 5 or 20 mg reduced LDL-C by an average of 67% to 76%. ODYSSEY KT[35] trial (2018) included patients from South Korea and Taiwan. Alirocumab versus placebo, on top of atorvastatin 40-80 mg, rosuvastatin 20, or simvastatin 40 mg, showed the least-square mean percentage change in LDL-C from baseline of −57.1% versus + 6.3%, with a statistically significant difference between the groups of −63.4%. Patients with diabetes mellitus (DM) on insulin therapy with either type 1 or 2 (T1DM or T2DM) were enrolled in the ODYSSEY DM-INSULIN[33] trial (2017). Alirocumab 75Q2W as an add-on to statins with or without other LLTs yielded a least-square mean percentage change in baseline LDL-C of −50.1% versus −1.3% of the patients on placebo with a significant difference between the diabetic groups of −49.0% in type 2 DM (T2DM) and − 47.8% in T1DM. The ODYSSEY DM-DYSLIPIDEMIA[34] study (2018) tested alirocumab 75Q2W in patients with T2DM and mixed dyslipidemia and CV risk factors. In the alirocumab group compared to the usual care group, there was a mean of −37.3% reduction in mean nonhigh-density lipoprotein cholesterol (non-HDL-C) versus −4.7% (difference of −32.5%, P < 0.0001) and LDL-C reduction by 43%. More than 66% of the patients achieved their non-HDL-C goals.

Evolocumab was studied in T2DM patients in the BERSON[48] trial (2019). Evolocumab combined with atorvastatin showed a significant reduction in LDL-C by ≥70% in both regimens (Q2W and QM). In a two-dose regimen, the EVOPACS[49] trial (2019) investigated evolocumab 420 mg QM in patients during hospitalization due to acute coronary syndrome (ACS). Evolocumab on top of high-dose statin showed a difference in mean percentage change from baseline LDL-C of −40.7% with 95.7% of the patients who achieved LDL-C <1.8 mmol/L (70 mg/dL) versus 37.6% on placebo. Finally, PCKS9 monoclonal antibodies are considered effective and safe in statin-intolerant patients, as reported in at least three[50],[51],[52] trials. Evolocumab in the GAUSS-2[50] (2014) and GAUSS-3[51] (2016) studies significantly reduced LDL-C by 53%–56% and 52.8%, respectively. Moreover, a significant LDL-C reduction by 45% was achieved with alirocumab use in the ODYSSEY ALTERNATIVE[52] trial (2015) at week 24. The aforementioned trials[50],[51],[52] defined statin intolerance as the inability to tolerate two or more statins at the lowest available dosage.

Familial hypercholesterolemia

Evolocumab in the RUTHERFORD-2[30] trial (2015), which recruited patients with HeFH and LDL-C of ≥ 2.58 mmol/L (100 mg/dL), significantly reduced baseline LDL-C by 61.3% (QM) and 59.2% (Q2W) at week 12. In ODYSSEY FH I and FH II[42] (2015), alirocumab as an add-on therapy to statins in patients with HeFH significantly reduced LDL-C by 57.9% and 51.4%, respectively, at week 24 through week 78. With a longer follow-up, the reported LDL-C reductions were 51.8% and 52.1% and the percentages of patients who achieved target LDL-C were 59.8% and 68.2%, respectively. Patients with HeFH and LDL-C ≥4.14 mmol/L (160 mg/dL) when started on alirocumab 150Q2W on top of statin in ODYSSEY HIGH FH[41] trial (2016) had a percent change in baseline LDL-C of −45.7% compared to −6.6% on placebo with a significant least square mean difference of − 39.1% at week 24 which maintained through week 78. The percentage of patients on alirocumab who achieved LDL-C targets was 41% as compared to 5.7% on placebo.

In the ODYSSEY OLE[43] study (2018), alirocumab led to an LDL-C reduction by 44.2% at week 8 that increased to 47.9% by week 96. The TAUSSIG[53] trial (2020) recruited patients with HoFH (35%) or severe HeFH (65%) who completed Part A or B of the TESLA study and administered evolocumab over 4 years. At weeks 12 and 216, patients with HoFH showed smaller relative reductions in LDL-C (−21.2% and −4%, respectively) when compared to that in patients with severe HeFH (−54.9% and −47.2%, respectively). In the TESLA-B[29] trial (2015), evolocumab (QM) on top of LLT significantly decreased LDL-C by 30.9% in HoFH patients after 12 weeks of therapy.

In patients with HeFH and/or coronary heart disease (CHD) on LLT and baseline LDL-C of ≥4.14 mmol/L (160 mg/dL), alirocumab 150Q2W reduced LDL-C levels by 55% at week 24 in the alirocumab expanded use program (2018).[36] Furthermore, in Japanese patients with HeFH or non-FH and high CV risk on statins, i.e., ODYSSEY JAPAN[39] trial (2016), there was a least-square mean change in baseline LDL-C of −62.5% in the alirocumab group versus + 1.6% in the placebo group at week 24 through 52 weeks with 96.7% of the patients achieving their LDL-C goals. In a pooled analysis[54] (2018) of four evolocumab 12-week trials (LAPLACE-2,[27] RUTHERFORD-2,[30] MENDEL-2,[31] and GAUSS-2[50]) including mixed patient populations, i.e., familial and primary hypercholesterolemia with different CV risks and prior statin intolerance, evolocumab as compared to placebo led to mean percent changes in LDL-C of −65.7% (Q2W) and −65.0% (QM). When compared to ezetimibe, the mean percent changes in LDL-C were −38.9% (Q2W) and −40.3% (QM).


   Cardiovacular Benefit Top


PCSK9 inhibition is an important process in controlling lipid levels to prevent primary or secondary CV incidents. The ODYSSEY LONG TERM[55] trial (2015) showed that alirocumab significantly lowered LDL-C by 62%, and the rate of major adverse CV events (MACE) by 48% (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.31–0.90; nominal P = 0.02). Similarly, evolocumab in the OSLER[56] study (2015) significantly reduced LDL-C by 61% and adverse CV events rate by 53% (HR, 0.47; 95% CI, 0.28–0.78; P = 0.003).

The multicenter double-blind FOURIER[57] trial, a large-scale CV outcome trial was published in 2017. The study enrolled 27,564 patients with ASCVD and LDL-C level of ≥1.8 mmol/L (70 mg/dL) who were on statin therapy across 49 countries. It investigated the effect of evolocumab (140 mg Q2W or 420 mg QM) in addition to statin therapy on CV events against matched placebo. In the evolocumab group, patients achieved a mean 59% reduction in LDL-C at 48 weeks and had a significantly reduced risk of the primary composite endpoint (HR, 0.85; 95% CI, 0.79–0.92; P < 0.001) at a median duration of follow-up of 26 months. The primary endpoint was a composite of CV death, myocardial infarction (MI), stroke, hospitalization for unstable angina (UA), or coronary revascularization. There was also a statistically significant reduction in the secondary endpoint of CV death, MI, or stroke (HR, 0.80; 95% CI, 0.73–0.88; P < 0.001) but not in CV death as an individual component.

In 2017, the combined analysis[58] of SPIRE-1 and SPIRE-2 trials was also published. The SPIRE-1 and SPIRE-2 trials were parallel multicenter, double-blind, randomized control trials that tested bococizumab in addition to statin therapy on CV events in patients at high risk for CV events. The primary endpoint was a composite of CV death, nonfatal MI, nonfatal stroke, and hospitalization for UA needing urgent revascularization. Patients in the SPIRE program developed high rates of antidrug antibodies (ADAs), and the combined analysis of the SPIRE-1 and SPIRE-2 trials did not show any benefit with regards to MACE rates. As a consequence, both SPIRE trials were discontinued prematurely by the sponsor in November 2016.[7],[58]

The ODYSSEY OUTCOMES[59] trial (2018) was a multicenter, double-blind, randomized control trial that investigated the effect of alirocumab (75 mg or 150 mg Q2W) on top of statin therapy on CV events. The study recruited 18,924 patients with LDL-C >1.8 mmol/L (70 mg/dL) and on a maximally tolerated dose of statin who had a recent ACS event across 57 countries. Alirocumab significantly lowered the primary endpoint of a composite of CV death, MI, stroke, hospitalization for UA, or coronary revascularization (HR, 0.85; 95% CI, 0.78–0.93; P < 0.001) over a median follow-up of 48 months with the absolute benefit among patients with baseline LDL-C of ≥2.58 mmol/L (100 mg/dL). The CV benefit of the PCSK9 monoclonal antibodies was related in part to the reduction in the levels of atherogenic lipids such as LDL-C, non-HDL-C, lipoprotein (a) (Lp(a)) and apolipoprotein B.[60] In addition, evolocumab on top statin therapy in the GLAGOV[61] study (2016) lowered the atheroma volume and led to plaque regression.


   Adverse Effects Top


Findings from PCSK9 monoclonal antibodies research did not find excess in muscle adverse symptoms or rise in creatinine kinase or liver enzyme levels which are commonly associated with statin therapy.[1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],[56],[57],[58],[59],[60] Nasopharyngitis and mild self-limited injection site reactions (e.g., itching, redness, and swelling) are considered the most frequent adverse reactions.[4],[59],[62]

Anti-drug antibodies (ADAs) can be generated in response to monoclonal antibodies either with the fully human (e. g., alirocumab and evolocumab) or the humanized (e.g., murine-derived bococizumab) type. Alirocumab and evolocumab did not lead to a significant ADAs generation unlike bococizumab which generated high-titer ADAs due to its high immunogenic property.[58],[63] The aforementioned difference explains the higher injection site reaction rate reported with bococizumab.[58] The very low LDL-C levels achieved with PCSK9 monoclonal antibodies have raised a concern about the association of their use with cognitive impairment,[64] such as delirium, attention disorders, amnesia, dementia, disturbances in thinking and perception, or mental impairment disorders.[4],[62]

Findings from the published literature did not find a statistically significant difference in terms of neurocognitive adverse events with alirocumab and evolocumab use when compared with the control.[1],[55],[57],[59],[60],[64] As previously suggested that a significant reduction in LDL-C levels with statin use may influence the glycemic status of the body and lead to an increase in diabetes incidence,[58],[65] the current body of evidence[1],[60],[65] did not prove that alirocumab[33],[55],[59],[66] nor evolocumab[48],[57],[67],[68],[69],[70] use would significantly increase the incidence of new-onset diabetes or worsen the preexisting diabetic condition.

Finally, there were no clinically meaningful changes in the levels of fat-soluble vitamins (e.g., Vitamin E or K) and steroid hormones in the studies that measured their levels as part of a prespecified safety analysis.[55],[71]


   Summary Top


The currently available PCSK9 monoclonal antibodies, alirocumab and evolocumab, are proved effective and safe when used alone or in addition to other LLTs in patients with hypercholesterolemia in the presence or absence of CV risk. The significant reduction in baseline LDL-C observed early with PCSK9 monoclonal antibodies therapy has been associated with positive CV outcomes but not mortality benefit. The safety profile of PCSK9 monoclonal antibodies is good since most of the reported adverse effects are mild and the reported neurocognitive adverse events in some studies are not statistically significant. PCSK9 monoclonal antibodies offer a safe and effective therapeutic option for patients who are intolerant to statin therapy or who have not achieved their LDL-C goals.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Karatasakis A, Danek BA, Karacsonyi J, Rangan BV, Roesle MK, Knickelbine T, et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: A meta-analysis of 35 randomized controlled trials. J Am Heart Assoc 2017;6:pii:e006910. doi: 10.1161/JAHA.117.006910.  Back to cited text no. 1
    
2.
Jones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: A retrospective analysis. J Am Heart Assoc 2012;1:e001800.  Back to cited text no. 2
    
3.
Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015;372:2387-97.  Back to cited text no. 3
    
4.
Rosenson RS, Hegele RA, Fazio S, Cannon CP. The evolving future of PCSK9 inhibitors. J Am Coll Cardiol 2018;72:314-29.  Back to cited text no. 4
    
5.
Landmesser U, Chapman MJ, Stock JK, Amarenco P, Belch JJF, Borén J, et al. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J 2018;39:1131-43.  Back to cited text no. 5
    
6.
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:e285-350.  Back to cited text no. 6
    
7.
Pfizer Press Release. Pfizer Discontinues Global Development of Bococizumab, Its Investigational PCSK9 Inhibitor. November, 2016. Available from: https://www.pfizer.com/news/press-release/press-release detail/pfizer_discontinues_global_development_of_bococizumab_its_investigational_pcsk9_inhibitor. [Last accessed on 2020 Feb 11].  Back to cited text no. 7
    
8.
Levisetti M, Joh T, Wan H, Liang H, Forgues P, Gumbiner B, et al. A phase I randomized study of a specifically engineered, pH-sensitive PCSK9 inhibitor RN317 (PF-05335810) in hypercholesterolemic subjects on statin therapy. Clin Transl Sci 2017;10:3-11.  Back to cited text no. 8
    
9.
Shen T, James DE, Krueger KA. Population pharmacokinetics (PK) and pharmacodynamics (PD) analysis of LY3015014, a monoclonal antibody to protein convertase subtilisin/kexin type 9 (PCSK9) in healthy subjects and hypercholesterolemia patients. Pharm Res 2017;34:185-92.  Back to cited text no. 9
    
10.
Budha NR, Leabman M, Jin JY, Wada DR, Baruch A, Peng K, et al. Modeling and simulation to support phase 2 dose selection for RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9. AAPS J 2015;17:881-90.  Back to cited text no. 10
    
11.
Baruch A, Luca D, Kahn RS, Cowan KJ, Leabman M, Budha NR, et al. A phase 1 study to evaluate the safety and LDL cholesterol-lowering effects of RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9. Clin Cardiol 2017;40:503-11.  Back to cited text no. 11
    
12.
Warden BA, Fazio S, Shapiro MD. The PCSK9 revolution: Current status, controversies, and future directions. Trends Cardiovasc Med 2020;30:179-85.  Back to cited text no. 12
    
13.
Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366:1108-18.  Back to cited text no. 13
    
14.
Dias CS, Shaywitz AJ, Wasserman SM, Smith BP, Gao B, Stolman DS, et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: Results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. J Am Coll Cardiol 2012;60:1888-98.  Back to cited text no. 14
    
15.
Gumbiner B, Joh T, Liang H, Wan H, Levisetti M, Vana AM, et al. The effects of single- and multiple-dose administration of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies. Cardiovasc Ther 2018;36:doi: 10.1111/1755-5922.12309.  Back to cited text no. 15
    
16.
Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891-900.  Back to cited text no. 16
    
17.
McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344-53.  Back to cited text no. 17
    
18.
Stein EA, Gipe D, Bergeron J, Gaudet D, Weiss R, Dufour R, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: A phase 2 randomised controlled trial. Lancet 2012;380:29-36.  Back to cited text no. 18
    
19.
Teramoto T, Kobayashi M, Uno K, Takagi Y, Matsuoka O, Sugimoto M, et al. Efficacy and safety of alirocumab in Japanese subjects (phase 1 and 2 studies). Am J Cardiol 2016;118:56-63.  Back to cited text no. 19
    
20.
Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, Plowchalk D, et al. Results 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 hypercholesterolemia. Am J Cardiol 2015;115:1212-21.  Back to cited text no. 20
    
21.
Fazio S, Robertson DG, Joh T, Wan H, Riel T, Forgues P, et al. Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin. Cardiovasc Ther 2018;36: doi: 10.1111/1755-5922.12308.  Back to cited text no. 21
    
22.
Yokote K, Kanada S, Matsuoka O, Sekino H, Imai K, Tabira J, et al. Efficacy and safety of bococizumab (RN316/PF-04950615), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic Japanese subjects receiving a stable dose of atorvastatin or treatment-naive- results from a randomized, placebo-controlled, dose-ranging study. Circ J 2017;81:1496-505.  Back to cited text no. 22
    
23.
Koren MJ, Scott R, Kim JB, Knusel B, Liu T, Lei L, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): A randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012;380:1995-2006.  Back to cited text no. 23
    
24.
Giugliano RP, Desai NR, Kohli P, Rogers WJ, Somaratne R, Huang F, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): A randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012;380:2007-17.  Back to cited text no. 24
    
25.
Raal F, Scott R, Somaratne R, Bridges I, Li G, Wasserman SM, et al. Low-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) randomized trial. Circulation 2012;126:2408-17.  Back to cited text no. 25
    
26.
Hirayama A, Honarpour N, Yoshida M, Yamashita S, Huang F, Wasserman SM, et al. Effects of evolocumab (AMG 145), a monoclonal antibody to PCSK9, in hypercholesterolemic, statin-treated Japanese patients at high cardiovascular risk—primary results from the phase 2 YUKAWA study. Circ J 2014;78:1073-82.  Back to cited text no. 26
    
27.
Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, et al. Effect 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 trial. JAMA 2014;311:1870-82.  Back to cited text no. 27
    
28.
Kiyosue A, Honarpour N, Kurtz C, Xue A, Wasserman SM, Hirayama A. A phase 3 study of evolocumab (AMG 145) in statin-treated Japanese patients at high cardiovascular risk. Am J Cardiol 2016;117:40-7.  Back to cited text no. 28
    
29.
Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): A randomised, double-blind, placebo-controlled trial. Lancet 2015;385:341-50.  Back to cited text no. 29
    
30.
Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): A randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331-40.  Back to cited text no. 30
    
31.
Koren MJ, Lundqvist P, Bolognese M, Neutel JM, Monsalvo ML, Yang J, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: The MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2531-40.  Back to cited text no. 31
    
32.
Stroes E, Guyton JR, Lepor N, Civeira F, Gaudet D, Watts GF, et al. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on statin therapy: The ODYSSEY CHOICE II study. J Am Heart Assoc 2016;5:pii:e003421.  Back to cited text no. 32
    
33.
Leiter LA, Cariou B, Müller-Wieland D, Colhoun HM, Del Prato S, Tinahones FJ, et al. Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM-INSULIN randomized trial. Diabetes Obes Metab 2017;19:1781-92.  Back to cited text no. 33
    
34.
Ray KK, Leiter LA, Müller-Wieland D, Cariou B, Colhoun HM, Henry RR, et al. Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes Obes Metab 2018;20:1479-89.  Back to cited text no. 34
    
35.
Koh KK, Nam CW, Chao TH, Liu ME, Wu CJ, Kim DS, et al. A randomized trial evaluating the efficacy and safety of alirocumab in South Korea and Taiwan (ODYSSEY KT). J Clin Lipidol 2018;12:162-72.  Back to cited text no. 35
    
36.
Glueck CJ, Brown A, Goldberg AC, McKenney JM, Kantaros L, Stewart J, et al. Alirocumab in high-risk patients: Observations from the open-label expanded use program. J Clin Lipidol 2018;12:662-8.  Back to cited text no. 36
    
37.
Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, et al. Efficacy 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 study. Am Heart J 2015;169:906-15.  Back to cited text no. 37
    
38.
Blom DJ, Hala T, Bolognese M, Lillestol MJ, Toth PD, Burgess L, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014;370:1809-19.  Back to cited text no. 38
    
39.
Teramoto T, Kobayashi M, Tasaki H, Yagyu H, Higashikata T, Takagi Y, et al. Efficacy and safety of alirocumab in Japanese patients with heterozygous familial hypercholesterolemia or at high cardiovascular risk with hypercholesterolemia not adequately controlled with statins- ODYSSEY JAPAN randomized controlled trial. Circ J 2016;80:1980-7.  Back to cited text no. 39
    
40.
Roth EM, Moriarty PM, Bergeron J, Langslet G, Manvelian G, Zhao J, et al. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis 2016;254:254-62.  Back to cited text no. 40
    
41.
Ginsberg HN, Rader DJ, Raal FJ, Guyton JR, Baccara-Dinet MT, Lorenzato C, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc Drugs Ther 2016;30:473-83.  Back to cited text no. 41
    
42.
Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;36:2996-3003.  Back to cited text no. 42
    
43.
Farnier M, Hovingh GK, Langslet G, Dufour R, Baccara-Dinet MT, Din-Bell C, et al. Long-term safety and efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia: An open-label extension of the ODYSSEY program. Atherosclerosis 2018;278:307-14.  Back to cited text no. 43
    
44.
Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, et al. Efficacy 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 trial. Eur Heart J 2015;36:1186-94.  Back to cited text no. 44
    
45.
Bays H, Gaudet D, Weiss R, Ruiz JL, Watts GF, Gouni-Berthold I, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab 2015;100:3140-8.  Back to cited text no. 45
    
46.
Farnier M, Jones P, Severance R, Averna M, Steinhagen-Thiessen E, Colhoun HM, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis 2016;244:138-46.  Back to cited text no. 46
    
47.
Roth EM, McKenney JM. ODYSSEY MONO: Effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol 2015;11:27-37.  Back to cited text no. 47
    
48.
Lorenzatti AJ, Eliaschewitz FG, Chen Y, Lu J, Baass A, Monsalvo ML, et al. Randomised study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Primary results of the BERSON clinical trial. Diabetes Obes Metab 2019;21:1455-63.  Back to cited text no. 48
    
49.
Koskinas KC, Windecker S, Pedrazzini G, Mueller C, Cook S, Matter CM, et al. Evolocumab for early reduction of LDL cholesterol levels in patients with acute coronary syndromes (EVOPACS). J Am Coll Cardiol 2019;74:2452-62.  Back to cited text no. 49
    
50.
Stroes E, Colquhoun D, Sullivan D, Civeira F, Rosenson RS, Watts GF, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: The GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014;63:2541-8.  Back to cited text no. 50
    
51.
Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, et al. Efficacy and tolerability of evolocumab vs. ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-90.  Back to cited text no. 51
    
52.
Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, et al. Efficacy and safety of alirocumab vs. ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol 2015;9:758-69.  Back to cited text no. 52
    
53.
Santos RD, Stein EA, Hovingh GK, Blom DJ, Soran H, Watts GF, et al. Long-term evolocumab in patients with familial hypercholesterolemia. J Am Coll Cardiol 2020;75:565-74.  Back to cited text no. 53
    
54.
Stroes E, Robinson JG, Raal FJ, Dufour R, Sullivan D, Kassahun H, et al. Consistent LDL-C response with evolocumab among patient subgroups in PROFICIO: A pooled analysis of 3146 patients from phase 3 studies. Clin Cardiol 2018;41:1328-35.  Back to cited text no. 54
    
55.
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99.  Back to cited text no. 55
    
56.
Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.  Back to cited text no. 56
    
57.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.  Back to cited text no. 57
    
58.
Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med 2017;376:1527-39.  Back to cited text no. 58
    
59.
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097-107.  Back to cited text no. 59
    
60.
Bai J, Gong LL, Li QF, Wang ZH. Long-term efficacy and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibodies: A meta-analysis of 11 randomized controlled trials. J Clin Lipidol 2018;12:277-91.  Back to cited text no. 60
    
61.
Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: The GLAGOV randomized clinical trial. JAMA 2016;316:2373-84.  Back to cited text no. 61
    
62.
Rosenson RS, Hegele RA, Koenig W. Cholesterol-lowering agents PCSK9 inhibitors today and tomorrow. Circ Res 2019;124:364-385.  Back to cited text no. 62
    
63.
Ridker PM, Tardif JC, Amarenco P, Duggan W, Glynn RJ, Jukema JW, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med 2017;376:1517-26.  Back to cited text no. 63
    
64.
Giugliano RP, Mach F, Zavitz K, Kurtz C, Im K, Kanevsky E, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med 2017;377:633-43.  Back to cited text no. 64
    
65.
Chen Q, Wu G, Li C, Qin X, Liu R, Zhang M. Safety of proprotein convertase subtilisin/kexin type 9 monoclonal antibodies in regard to diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. Am J Cardiovasc Drugs 2019. doi: 10.1007/s40256-019-00386-w.  Back to cited text no. 65
    
66.
Colhoun HM, Ginsberg HN, Robinson JG, Leiter LA, Müller-Wieland D, Henry RR, et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. Eur Heart J 2016;37:2981-9.  Back to cited text no. 66
    
67.
Koren MJ, Sabatine MS, Giugliano RP, Langslet G, Wiviott SD, Ruzza A, et al. Long-term efficacy and safety of evolocumab in patients with hypercholesterolemia. J Am Coll Cardiol 2019;74:2132-46.  Back to cited text no. 67
    
68.
Blom DJ, Koren MJ, Roth E, Monsalvo ML, Djedjos CS, Nelson P, et al. Evaluation of the efficacy, safety and glycaemic effects of evolocumab (AMG 145) in hypercholesterolaemic patients stratified by glycaemic status and metabolic syndrome. Diabetes Obes Metab 2017;19:98-107.  Back to cited text no. 68
    
69.
Sattar N, Toth PP, Blom DJ, Koren MJ, Soran H, Uhart M, et al. Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus. Am J Cardiol 2017;120:1521-7.  Back to cited text no. 69
    
70.
Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: A prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017;5:941-50.  Back to cited text no. 70
    
71.
Blom DJ, Djedjos CS, Monsalvo ML, Bridges I, Wasserman SM, Scott R, et al. Effects of evolocumab on Vitamin E and steroid hormone levels: Results from the 52-week, phase 3, double-blind, randomized, placebo-controlled DESCARTES study. Circ Res 2015;117:731-41.  Back to cited text no. 71
    




 

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