PCSK9 Inhibitors

A therapy in cardiovascular risk reduction.

LDL cholesterol remains the key target for lipid lowering and current therapies are targeted at reducing the rate of cholesterol biosynthesis (statins) or reducing the rate of absorption of cholesterol into the circulation (ezetimibe, bile acids).  Statins have been proven to reduce LDL cholesterol and cardiovascular disease in randomised controlled trials. However, new treatments are in development to address those who may still be at risk from cardiovascular disease, even after current intensive treatment (known as residual risk).

There can be considerable variation and unpredictability in an individual’s response to taking a statin and research has shown that 10-15% of patients treated with a statin show some degree of intolerance, with many people stopping their statin within a year of its prescription.  Other research showed that 33% of patients in outpatient clinics did not reach their target reductions in non HDL cholesterol/goals, and in patients with familial hypercholesterolaemia (FH), high intensity statins can reduce LDL cholesterol by only 50% at maximum and in general monotherapy with statins is not usually sufficient to get an FH patient to goal.   Those who have raised LDL cholesterol not due to FH are also not achieving goals on current treatments, leaving a burden on CVD morbidity and mortality even after treatment.   Treatments are required that can also provide reductions in other atherogenic lipoproteins such as VLDL remnants  and Lipoprotein (a). 


What are PCSK9 inhibitors?


The LDL receptor (LDLR) is found on the surface of the liver and is an essential component for regulating LDL cholesterol levels in the circulation. As part of its natural catabolism (or metabolic pathway), LDL cholesterol binds to the LDL receptor where it is taken inside the cell resulting in its removal from the circulation.  The LDL receptor can then be recycled back to the cell surface where it can bind with more LDL cholesterol, thus controlling levels of LDL cholesterol.

PCSK9 or proproptein convertase substilisin/kexin type 9 is a protein mainly produced by hepatocytes in the liver (and to a lesser extent by the intestine, kidneys and brain). It is a key regulator of LDL receptor levels and will bind to LDL receptors with a high affinity.  It is this binding process which results in the LDL receptor being degraded or destroyed.  Normally the LDL receptor is continuously recycled but when PCSK9 is present it is bound to it and then taken into the cell for degradation (or destruction) which then stops the recycling of the receptor back to the cell surface.  Therefore the presence of PCSK9 increases the probability of the LDL receptor being destroyed. This results in fewer LDL receptors available on the liver cell surface to bind to circulating LDL cholesterol, and therefore LDL cholesterol levels will increase.


There are "loss of function" and "gain of function" mutations of the PCSK9 gene. What are they and how are they relevant?


Research shows patients can have different mutations within the PCSK9 gene which can alter PCSK9 function and in turn will affect LDL cholesterol levels.  These mutations or polymorphisms can be divided into “loss of function” mutations and “gain of function” mutations

Loss of function mutations (LOF):

Those with a loss of function mutation of PCSK9 account for  2% of the population. LOF mutations in PCSK9 leads to decreased PCSK9 function which affects its ability to lower the amount of LDL receptors on the surface of the liver surface.   As a result, a LOF mutation can decrease LDL cholesterol levels and reduce the risk of cardiovascular event.  People with loss of function PCSK9 mutations have a lifelong reduction in their LDL cholesterol levels, and appear to be genuinely healthy with no apparent adverse pathological consequences arising from this.

Gain of Function mutations (GOF):

In comparison, gain of function mutations leads to increased PCSK9 activity and is associated with higher levels of LDL cholesterol in the circulation due to the increased removal of LDL receptors for degradation.   There are 3 known gain of function mutations of PCSK9 variants which leads to increased PCSK9 activity, which in turn increase the destruction of the LDL receptors. The more degradation of the LDL receptor the slower LDL cholesterol clearance from the circulation, which leads to increased LDL cholesterol and risk of CVD. 

Gain of function mutations of PCSK9 have been associated with heterozygous FH, characterised by lifelong elevation of LDL cholesterol levels, early development of atherosclerosis and increased risk of cardiovascular events.  Therefore, reducing the activity or expression of PCSK9 increases the number of LDL receptors which in turn can reduce levels of circulating LDL cholesterol.  


What are monoclonal antibodies and how do they work?


Monoclonal antibodies have become an important tool in biochemistry, molecular biology and medicine and are a type of biological therapy.  Monoclonal means one type so each monoclonal antibody drug is a lot of copies of one specific type of antibody and it is possible to produce monoclonal antibodies for any given substance that will then specifically bind to that particular substance.  They are currently used in anti -cancer treatments and auto-immune diseases such as rheumatoid arthritis, Crohns disease etc.

The PCSK9 inhibitors are monoclonal antibodies  that target and inactivate the PCSK9 protein.  They work by inhibiting PCSK9, which then prevents it binding to LDL receptors which stops them being degraded and therefore allows the LDL receptor to be recycled back to the surface of the liver, promoting the removal of LDL cholesterol from the circulation. 

Therapies such as statins actually stimulate the production of PCSK9, which limits their own ability to lower LDL cholesterol.  Blocking the PCSK9 pathway up-regulates the recycling of LDL receptors so PCSK9 inhibitors have the potential to produce further improvements in the outcome of those patients with persistent elevations of LDL cholesterol despite taking high intensity statins.


What are the advantages of treatment with monoclonal antibodies?


-Monoconal antibodies have a high specificity for a particular unique target. 

-They have an increased potency which means less frequency of dosing is required i.e. once or twice a month depending on dose. 

-They have a low drug-drug interaction

-They are unlikely to cause ECG changes (such as QT interval changes)

-As they are large molecules, they do not cross the blood brain barrier (the brain’s selective barrier which allows in only essential molecules to the brain).


What are the names of the current PCSK9 inhibitors?


When monoclonal antibodies are used in medications, the non -proprietary name of the medication ends in “mab”

Currently, the two most advanced PCSK9 inhibitors are:

Evolocumab (proprietary name) or  Repatha ( trade name) – produced by Amgen

Alirocumab (proprietary name) or  Praluent (trade name)  – produced by Sanofi/Regeneron


Who would benefit from PCSK9 inhibitors?


All PCSK9 treatments are seen as an adjunct to diet and maximally tolerated statin therapy. The National Institute for Health and Care Excellence (NICE) published guidance  in 2016 recommending Evolocumab and Alirocumab for some people who have conditions that put them at extremely high risk of heart attacks or strokes.

The guidance recommends the medication for adults with primary hypercholesterolaemia/mixed dyslipidaemia and those with heterozygous familial hypercholesterolaemia (HeFH) ​to help reduce their risk of cardiovascular disease. The table below shows this in more detail:

Furthermore the drugs are recommended for people whose cholesterol levels are not controlled adequately using other drugs such as statins, or who can’t tolerate statins because of their side effects or have another condition which means they can’t take them.


How are they administered and how often do they need to be given?


They are self administered by subcutaneous injection (pre-filled pen or syringe) either once a month or once every two weeks:

Evolocumab: sub cutaneous injection every 2 weeks (140mg dose) or once a month using 420mg dose

Alirocumab: sub cutaneous injection every 2 weeks in either 75mg or 150mg doses (from trial data majority of patients achieved their LDL lowering goals with the 75mg dose when added to statin (phase 3 ODYSSEY clinical trial) and 150mg dose reduced LDL by 58%


What are the main side effects of the treatment?


PCSK9 inhibitors appear to be well tolerated by patients.  Common side effects reported include flu like symptoms, cold, nausea, back and joint pain, injection site reactions and muscle related pain.


Where can I get more information on PCSK9 


All health care professionals can sign up to the PCSK9 Forum for the most up to date information on PCSK9 inhibitors, research trial data and the latest clinical findings presented at meetings such as the EAS and ESC 

You can sign up at: http://www.pcsk9forum.org/