PCSK9 inhibitory new hope for patients with

hypercholesterolemia ?

Nasim BadarnaUPJS

kosice, slovakia

Structure of the diploma thesis

• Introduction• Hyperlipidemia and

Hypercholesterolemia• Current treatment • LDL-receptors• PCSK9 – new hope ? • Clinical trial • Conclusion

introduction • Cholesterol is a fatty substance that occurs naturally in

the body. Providing vital functions throughout our bodies(cell membrane and certain hormones e.c.t).

• However, these cholesterol levels should by kept in a specific range otherwise it can cause serious medical problems such as heart attack .

Introduction • familial hypercholesterolemia (Heterozygous FH), is

one of the most common genetic disorders in humans, affecting ≈12 million people worldwide, and so, hypercholesterolemic patients are advised to use pharmacological drugs that lowers the levels of cholesterol achieve optimal level goals.

• PCSK9, Proprotein convertase subtilisin/kexin type 9, is a new class of drugs that have been shown to dramatically lower LDL cholesterol levels which we will discuss in details in this presentation.

Hypercholesterolemia• is characterized by elevated low-density

lipoprotein cholesterol (LDL) in the blood.• Hypercholesterolemia is typically due to a

combination of environmental and genetic factors.[9] Environmental factors include obesity, diet, and stress.

• familial hypercholesterolemia (Heterozygous FH), In >98% of patients, the defect is caused by loss-of-function mutations in the LDL receptor.

• UK National Health Service recommends upper limits of total cholesterol of 5 mmol/L, and low-density lipoprotein cholesterol (LDL) of 3 mmol/L.

• There is five major groups of lipoprotein.

• Clinically 2 important; LDL and HDL

LDL HDL•  LDL is bad-cholesterol • HDL is a good

cholesterol.

• transports cholesterol from liver to peripheral tissues.

• HDL helps remove cholesterol from your arteries.

•  LDL is taken up by peripheral tissues by receptor-mediated endocytosis.

• Transports cholesterol from peripheral tissues to liver.

• LDL receptors are present in all tissues, But most abundant in hepatic cells. 

• Cholesterol is excreted through bile.

LDL & its clinical significance•  cardiovascular diseases. • It is the main source of cholesterol buildup

and blockage in the arteries, This is starting event of atherosclerosis, leading to MI.

• myocardial infarction before the age of 40 in men and before the age of 60 in women

•  • That’s why is crucial to manage levels of

high cholesterol.

Current treatments • Statins, ezetimibe, newer bile acid

sequestrants have resulted in significant improvements in the treatment of HeFH over the past 2 decades, with apparent reductions in cardiovascular morbidity and mortality.

• Statins, works by  inhibiting the enzyme HMG-CoA reductase which plays a central role in the production of cholesterol. 

Why bother? • Despite treatment with statins or

other lipid-modifying drugs, many HeFH patients do not achieve optimal LDL goals.

• Another disadvantage is that these drugs have significant side effects such as muscle pain, increased risk of diabetes mellitus.

PCSK9 role in LDL-receptors• PCSK9 = Proprotein convertase

subtilisin/kexin type 9.• The LDL receptor, binds and initiates ingestion of

LDL-particles from extracellular into cells, thus reducing LDL concentrations in plasma. And then the receptor is recycled back to the cell membrane surface to bind and ingest more LDL-particles.

•  However, when PCSK9 is bound to the LDLR & LDL particle complex, the receptor is degraded and is no longer recycled back to the cell membrane surface to bind and ingest more LDL-particles.

PCSK9 inhibition • Blocking PCSK9 binding to the LDL

receptor has recently been shown to be effective in lowering LDL-C in humans.

• AMG 145(PCSK9 Inhibitory) is a fully human monoclonal antibody to PCSK9 that yielded LDL-C reductions up to 81%.  optimal LDL levels

• Blocking PCSK9 receptors are recycled back to cell membrane to bind and ingest more LDL-particles lowering LDL levels in the plasma

It’s New ! • The first two PCSK9 inhibitors,

alirocumab and evolocumab, were approved as once every two week injections, subcutaneously, by the U.S. Food and Drug Administration in 2015.

Clinical trail• Relationships Between Plasma PCSK9 Levels,

LDL-cholesterol Concentrations and Lipoprotein (a) Levels in Familial Hypercholesterolemia

• This study has been completed.• Location:• Canada, Quebec; institute of nutrition and Functional

foods(INAF).• Sponsor.• Laval University• Information provided by (Responsible Party):• Patrick Couture, Laval University• ClinicalTrials.gov Identifier:• First received: August 22, 2014•

ClinicalTrials.gov , A service of the U.S. National Institutes of Heal

• Objective: is to examine to what extent variations in LDL-C and Lipoprotein (Lp) (a) concentrations are related to PCSK9 levels in hypercholesteremic patients.

• primary hypothesis: is that PCSK9  levels have a significant impact on LDL- C concentration variability and are associated with Lp(a) levels.

EligibilityCriteriaInclusion Criteria:Subjects with familial hypercholesterolemia:•Aged between 18-65 years•Carrier of a mutation in the LDL receptor geneExclusion Criteria:•Subjects with a previous history of cardiovascular disease•Subjects with Type 2 diabetes•Subjects with a history of cancer•Subjects with acute liver disease, hepatic dysfunction, or persistent elevations of serum transaminases•Subjects with a secondary hyperlipidemia due to any cause•History of alcohol or drug abuse within the past 2 years

RESULTS• evolocumab was intreduced to the FDA in

August 2014. The FDA approved evolocumab injection on 27 August 2015, for some patients who are unable to get their LDL cholesterol under control with current treatment options. 

• Side effects that occurred in 2% of people include nose and throat irritation, injection site reactions and bruising, flu-like symptoms, urinary tract infection, diarrhea, bronchitis and cough, and muscle pain

Conclusion • PCSK9 inhibitors administration yielded

rapid and substantial reductions in LDL-C in heterozygous familial hypercholesterolemia patients, with minimal adverse events and good tolerability.

• A new drug that enhances and improves the lives of many which indeed needed help…

• http://circ.ahajournals.org/content/126/20/2408.short

• http://circ.ahajournals.org/content/126/20/2408.short

REFERENCES• 1.↵ Goldstein JL, • Hobbs HH, • Brown MS• . Familial hypercholesterolemia. The Metabolic and

Molecular Bases of Inherited Disease. 2001:2863–2913.• Google Scholar• 2.↵ Slack J• . Risks of ischaemic heart-disease in familial

hyperlipoproteinaemic states. Lancet. 1969;2:1380–1382.• 3.↵ Leigh SE, • Foster AH, • Whittall RA, • Hubbart CS, • Humphries SE

•  Update and analysis of the University College London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet. 2008;72:485–498.

• CrossRefMedlineGoogle Scholar• 4.↵ Innerarity TL, • Weisgraber KH, • Arnold KS, • Mahley RW, • Krauss RM, • Vega GL, • Grundy SM• . Familial defective apolipoprotein B-100: low density

lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A. 1987;84:6919–6923.

• Abstract/FREE Full TextGoogle Scholar