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Article ; Online: Proprotein convertase subtilisin/kexin type 9: from genetics to clinical trials.

Stoekenbroek, Robert M / Kastelein, John J P

2018 Volume 33, Issue 3, Page(s) 269–275

Abstract: Purpose of review: This review describes the pivotal role of genetic insights and technologies in the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the rapid development of PCSK9 inhibitors - a revolutionary new class of lipid- ... ...

Abstract	Purpose of review: This review describes the pivotal role of genetic insights and technologies in the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the rapid development of PCSK9 inhibitors - a revolutionary new class of lipid-lowering agents. Recent findings: PCSK9 was discovered as a the third gene implicated in familial hypercholesterolemia. Population genetics studies, enabled by technological advances, were instrumental in validating PCSK9 as a therapeutic target. Monoclonal antibodies against PCSK9 were introduced in the clinic after an unprecedently rapid development path, in which clinical trial results confirmed that these drugs robustly lower cholesterol and improve clinical outcomes regardless of disease indication or background therapy. New strategies to PCSK9 inhibition are underway and have delivered promising preliminary results, including inhibition of PCSK9 synthesis by targeting the cellular gene expression machinery and vaccination. The future will tell whether directly targeting the genome through editing techniques will ultimately enable us to virtually eliminate many of the traditional CVD risk factors. Summary: The extraordinary PCSK9 narrative highlights the opportunities offered by genetics-driven drug development and holds valuable lessons for future development programs.
MeSH term(s)	Anticholesteremic Agents/therapeutic use ; Cholesterol/blood ; Clinical Trials as Topic ; DNA/genetics ; DNA Mutational Analysis ; Genetic Therapy/methods ; Humans ; Hypercholesterolemia/blood ; Hypercholesterolemia/genetics ; Hypercholesterolemia/therapy ; Mutation ; Proprotein Convertase 9/genetics ; Proprotein Convertase 9/metabolism ; Risk Factors
Chemical Substances	Anticholesteremic Agents ; DNA (9007-49-2) ; Cholesterol (97C5T2UQ7J) ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2018-03-21
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	645186-x
ISSN	1531-7080 ; 0268-4705
ISSN (online)	1531-7080
ISSN	0268-4705
DOI	10.1097/HCO.0000000000000517
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Zs.A 2556: Show issues

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Article ; Online: Can we afford not to screen for FH?

Stoekenbroek, Robert M / Kastelein, John J P / Hovingh, G Kees

European heart journal

2017 Volume 38, Issue 23, Page(s) 1840–1842

MeSH term(s)	Cost-Benefit Analysis ; Humans ; Hyperlipoproteinemia Type II ; Mutation ; United Kingdom
Language	English
Publishing date	2017-04-20
Publishing country	England
Document type	Editorial ; Comment
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehx197
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Zs.A 1563: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 640: Show issues

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Article ; Online: Dyslipidaemia: Statin-associated muscle symptoms - really all in the mind?

Stoekenbroek, Robert M / Kastelein, John J P

Nature reviews. Cardiology

2017 Volume 14, Issue 8, Page(s) 445–446

MeSH term(s)	Clinical Decision-Making ; Dyslipidemias/drug therapy ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Medication Therapy Management ; Muscular Diseases/chemically induced ; Muscular Diseases/physiopathology ; Muscular Diseases/psychology ; Muscular Diseases/therapy ; Nocebo Effect
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors
Language	English
Publishing date	2017-06-15
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2490375-9
ISSN	1759-5010 ; 1759-5002
ISSN (online)	1759-5010
ISSN	1759-5002
DOI	10.1038/nrcardio.2017.92
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Zs.A 6019: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 98: Show issues

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Article ; Online: Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program.

Stoekenbroek, Robert M / Kallend, David / Wijngaard, Peter Lj / Kastelein, John Jp

Future cardiology

2018 Volume 14, Issue 6, Page(s) 433–442

Abstract: Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi. Phase I and II data show that inclisiran lowers low-density lipoprotein cholesterol levels on average by >50% with a duration of ...

Abstract	Inclisiran is a novel drug that inhibits PCSK9 synthesis specifically in the liver, harnessing the natural mechanism of RNAi. Phase I and II data show that inclisiran lowers low-density lipoprotein cholesterol levels on average by >50% with a duration of effect that enables twice-yearly dosing. Phases I, II and emerging Phase III data support inclisiran's safety, tolerability and risk-benefit profile. The ongoing ORION program includes Phase III trials that will provide robust evidence of inclisiran's safety and efficacy in individuals at high risk of atherosclerotic cardiovascular disease (ASCVD), including established ASCVD and familial hypercholesterolemia. In addition, the ORION-4 trial will assess the impact of inclisiran on cardiovascular outcomes in approximately 15,000 ASCVD subjects.
MeSH term(s)	Cardiovascular Diseases/drug therapy ; Clinical Trials as Topic ; Drug Development ; Humans ; RNA, Small Interfering/pharmacology
Chemical Substances	ALN-PCS ; RNA, Small Interfering
Language	English
Publishing date	2018-10-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2274267-0
ISSN	1744-8298 ; 1479-6678
ISSN (online)	1744-8298
ISSN	1479-6678
DOI	10.2217/fca-2018-0067
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Zs.A 6836: Show issues

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Article ; Online: Inhibiting PCSK9 - biology beyond LDL control.

Stoekenbroek, Robert M / Lambert, Gilles / Cariou, Bertrand / Hovingh, G Kees

Nature reviews. Endocrinology

2018 Volume 15, Issue 1, Page(s) 52–62

Abstract: Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly ... ...

Abstract	Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly from the liver, but the protein is also expressed in the pancreas, the kidney, the intestine and the central nervous system. Although PCSK9 modulates cholesterol metabolism by regulating LDL receptor expression in the liver, in vitro and in vivo studies have suggested that PCSK9 is involved in various other physiological processes. Although therapeutic PCSK9 inhibition could theoretically have undesired effects by interfering with these non-cholesterol-related processes, studies of individuals with genetically determined reduced PCSK9 function and clinical trials of PCSK9 inhibitors have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation. The clinical implications of PCSK9 functions beyond lipid metabolism in terms of wanted or unwanted effects of therapeutic PCSK9 inhibition therefore appear to be limited. The objective of this Review is to describe the physiological role of PCSK9 beyond the LDL receptor to provide a rational basis for monitoring the effects of PCSK9 inhibition as these drugs gain traction in the clinic.
MeSH term(s)	Biomarkers/metabolism ; Cardiovascular Diseases/prevention & control ; Cholesterol, LDL/drug effects ; Cholesterol, LDL/metabolism ; Female ; Humans ; Hypercholesterolemia/drug therapy ; Hypercholesterolemia/prevention & control ; Lipid Metabolism/drug effects ; Male ; Proprotein Convertase 9/drug effects ; Proprotein Convertase 9/metabolism ; Receptors, LDL/drug effects ; Receptors, LDL/metabolism ; Sensitivity and Specificity
Chemical Substances	Biomarkers ; Cholesterol, LDL ; Receptors, LDL ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-)
Language	English
Publishing date	2018-10-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2489381-X
ISSN	1759-5037 ; 1759-5029
ISSN (online)	1759-5037
ISSN	1759-5029
DOI	10.1038/s41574-018-0110-5
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Zs.A 6336: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 93: Show issues

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Article ; Online: Homozygous familial hypercholesterolaemia: light at the end of the tunnel.

Stoekenbroek, Robert M / Kees Hovingh, G / Kastelein, John J P

European heart journal

2017 Volume 39, Issue 14, Page(s) 1169–1171

MeSH term(s)	Anticholesteremic Agents ; Cholesterol ; Homozygote ; Humans ; Hyperlipoproteinemia Type II
Chemical Substances	Anticholesteremic Agents ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2017-10-07
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	603098-1
ISSN	1522-9645 ; 0195-668X
ISSN (online)	1522-9645
ISSN	0195-668X
DOI	10.1093/eurheartj/ehx438
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Zs.A 1563: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 640: Show issues

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Article ; Online: Moving Targets: Recent Advances in Lipid-Lowering Therapies

Larsen, Lars E / Stoekenbroek, Robert M / Kastelein, John J P / Holleboom, Adriaan G

Arteriosclerosis, thrombosis, and vascular biology

2019 Volume 39, Issue 3, Page(s) 349–359

Abstract: Statin therapy has delivered tremendous value to society by improving the burden of atherosclerotic cardiovascular disease. Nonetheless, atherosclerotic cardiovascular disease remains the leading cause of death globally. Technological advances such as in ...

Abstract	Statin therapy has delivered tremendous value to society by improving the burden of atherosclerotic cardiovascular disease. Nonetheless, atherosclerotic cardiovascular disease remains the leading cause of death globally. Technological advances such as in the field of genomics have revolutionized drug discovery and development and have revealed novel therapeutic targets to lower low-density lipoprotein cholesterol (LDL-C), as well as other detrimental lipids and lipoproteins. Therapeutic LDL-C lowering prevents atherosclerotic cardiovascular disease with an effect size proportional to absolute LDL-C reductions and time of exposure. This understanding supports the notion that reducing cumulative LDL-C exposure should be a key therapeutic target. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibiting monoclonal antibodies provides the possibility of reducing LDL-C to very low levels. Novel therapeutic platforms such as RNA inhibition present opportunities to combine robust lipid lowering with infrequent dosing regimens, introducing therapies with vaccine-like properties. The position of lipid-lowering therapies with targets other than LDL-C, such as Lp(a) [lipoprotein(a)], TRL (triglyceride-rich lipoproteins), and remnant cholesterol, will likely be determined by the results of ongoing clinical trials. Current evidence suggests that reducing Lp(a) or TRLs could attenuate atherosclerotic cardiovascular disease risk in specific categories of patients. This review provides an overview of the latest therapeutic developments, focusing on their mechanisms, efficacy, and safety.
MeSH term(s)	Animals ; Atherosclerosis/etiology ; Atherosclerosis/prevention & control ; Clinical Trials as Topic ; Drug Design ; Drug Discovery ; Drug Evaluation, Preclinical ; Dyslipidemias/complications ; Dyslipidemias/drug therapy ; Eicosapentaenoic Acid/therapeutic use ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/therapeutic use ; Humans ; Hypolipidemic Agents/pharmacology ; Hypolipidemic Agents/therapeutic use ; Molecular Targeted Therapy ; Oligonucleotides, Antisense/pharmacology ; Oligonucleotides, Antisense/therapeutic use ; PPAR alpha/drug effects
Chemical Substances	Enzyme Inhibitors ; Hypolipidemic Agents ; Oligonucleotides, Antisense ; PPAR alpha ; Eicosapentaenoic Acid (AAN7QOV9EA)
Language	English
Publishing date	2019-02-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.118.312028
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Zs.A 1705: Show issues

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Article ; Online: New Drugs for Atherosclerosis.

Bruikman, Caroline S / Stoekenbroek, Robert M / Hovingh, G Kees / Kastelein, John P

The Canadian journal of cardiology

2017 Volume 33, Issue 3, Page(s) 350–357

Abstract: Atherosclerosis, the underlying process that ultimately leads to clinical cardiovascular disease (CVD), is caused by the multifactorial interaction of various conditions, and dyslipidemia is widely acknowledged as 1 of the crucial risk factors in this ... ...

Abstract	Atherosclerosis, the underlying process that ultimately leads to clinical cardiovascular disease (CVD), is caused by the multifactorial interaction of various conditions, and dyslipidemia is widely acknowledged as 1 of the crucial risk factors in this process. Statin drugs have been shown to decrease low-density lipoprotein cholesterol and CVD morbidity as well as mortality and are therefore pivotal in CVD prevention. Despite the use of statin drugs, CVD remains a leading cause of mortality worldwide, which suggests that additional lipid-lowering therapies are warranted. Several novel therapeutic agents, which are described in this review, are now well on their way in their respective development paths and might revolutionize anti-atherosclerotic drug therapy.
MeSH term(s)	Atherosclerosis/blood ; Atherosclerosis/drug therapy ; Drugs, Investigational/therapeutic use ; Humans ; Hypolipidemic Agents/therapeutic use ; Lipids/blood
Chemical Substances	Drugs, Investigational ; Hypolipidemic Agents ; Lipids
Language	English
Publishing date	2017-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	632813-1
ISSN	1916-7075 ; 0828-282X
ISSN (online)	1916-7075
ISSN	0828-282X
DOI	10.1016/j.cjca.2016.09.010
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Zs.A 2150: Show issues

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Article ; Online: Response to Comments on Santema et al. Hyperbaric Oxygen Therapy in the Treatment of Ischemic Lower-Extremity Ulcers in Patients With Diabetes: Results of the DAMO

Santema, Katrien T B / Stoekenbroek, Robert M / Koelemay, Mark J W / Ubbink, Dirk T

Diabetes care

2018 Volume 41, Issue 4, Page(s) e62–e63

MeSH term(s)	Diabetic Foot ; Humans ; Hyperbaric Oxygenation ; Ischemia ; Ulcer
Language	English
Publishing date	2018
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	441231-x
ISSN	1935-5548 ; 0149-5992
ISSN (online)	1935-5548
ISSN	0149-5992
DOI	10.2337/dci17-0059
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Zs.A 1434: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 365: Show issues

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Article ; Online: Inclisiran Durably Lowers Low-Density Lipoprotein Cholesterol and Proprotein Convertase Subtilisin/Kexin Type 9 Expression in Homozygous Familial Hypercholesterolemia: The ORION-2 Pilot Study.

Hovingh, G Kees / Lepor, Norman E / Kallend, David / Stoekenbroek, Robert M / Wijngaard, Peter L J / Raal, Frederick J

Circulation

2020 Volume 141, Issue 22, Page(s) 1829–1831

MeSH term(s)	Anticholesteremic Agents/therapeutic use ; Cholesterol, LDL/biosynthesis ; Ezetimibe/therapeutic use ; Gene Knockdown Techniques ; Genetic Therapy ; Homozygote ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; Hyperlipoproteinemia Type II/drug therapy ; Hyperlipoproteinemia Type II/genetics ; Hyperlipoproteinemia Type II/metabolism ; Hyperlipoproteinemia Type II/therapy ; Molecular Targeted Therapy ; Pilot Projects ; Proof of Concept Study ; Proprotein Convertase 9/antagonists & inhibitors ; Proprotein Convertase 9/biosynthesis ; Proprotein Convertase 9/genetics ; RNA Interference ; RNA, Small Interfering/adverse effects ; RNA, Small Interfering/genetics ; RNA, Small Interfering/pharmacology ; RNA, Small Interfering/therapeutic use ; Treatment Outcome
Chemical Substances	ALN-PCS ; Anticholesteremic Agents ; Cholesterol, LDL ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; RNA, Small Interfering ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Ezetimibe (EOR26LQQ24)
Language	English
Publishing date	2020-06-01
Publishing country	United States
Document type	Letter ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	80099-5
ISSN	1524-4539 ; 0009-7322 ; 0069-4193 ; 0065-8499
ISSN (online)	1524-4539
ISSN	0009-7322 ; 0069-4193 ; 0065-8499
DOI	10.1161/CIRCULATIONAHA.119.044431
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