PCSK9 Inhibitors

A new 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).

Why do we need further treatments for lowering cholesterol?

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). 

This has led to the development of “novel” treatments such as the PCSK9 inhibitors.  We ask some of the main questions about this new treatment below, and include summaries of the latest clinical findings and ongoing outcome studies.


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

A number of additional PCSK9 inhibitors are currently in clinical development.


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 a final draft guidance on May 5th 2016 recommending two already licenced PCSK9 inhibitors (Evolocumab and Alirocumab) for some people who have conditions that put them at extremely high risk of heart attacks or strokes.

The draft guidance recommends Alirocumab (Praluent, Sanofi) and Evolocumab (Repatha, Amgen) 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.

Until final guidance is issued, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance on a technology, it replaces local recommendations across the country.


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. 

Safety data is available from OSLER trials for evolocumab and ODYSSEY long term for alirocumab.  In both trials, adverse events reported by patients receiving PCSK9 inhibitors were similar when compared with those taking a placebo.  In other trial data for evolocumab, there was a slight excess of injection site reactions and muscle related events with evolocumab compared to placebo.

The US Food and Drug Administration (FDA) raised concerns regarding the possibility of adverse effects on cognition and it was unclear whether this was specifically related to the PCSK9 agents or the lowering of LDL cholesterol.   In the clinical trials, the incidence of neurocognitive events was 0.8%  for alirocumab and 0.7%  for placebo when added to a statin, and for evolocumab this was 0.1% compared to 0.3% in the control groups.


Summary of main clinical findings from 2015


Results from phase III clinical trials for both evolocumab and alirocumab have shown marked reductions in LDL cholesterol in people with FH or hypercholesterolaemia due to another cause, with further LDL cholesterol reductions when PCSK9 inhibitors are added to existing lipid lowering treatments such as high intensity statins.

In a summary of  reports, treatment with alirocumab or evolocumab, on top of conventional lipid lowering therapy including statins resulted in consistent lowering of LDL cholesterol (by about 60%), as well as about 50% reduction in major cardiovascular events. Definitive results are awaited from ongoing outcomes studies with the PCSK9 inhibitors, the first of which – FOURIER (evolocumab) – is anticipated later this year (details below).

Lipoprotein (a), an atherogenic lipoprotein linked with increased risk of cardiovascular disease showed significant reductions of between 28% and 32%.  One study also showed modest decreases in triglycerides and VLDL cholesterol, depending on dosing and significant increases in HDL cholesterol in parallel. 

In a meta-analysis by Navarese et al of 24 randomised controlled trials (RCTs) including over 10,000 patients treated with alirocumab or evolocumab, LDL cholesterol was reduced by about 50%. Additionally, PCSK9 inhibitor treatment was also associated with reduction in all-cause mortality by 55% (p=0.015), cardiovascular mortality by 50% (p=0.084) and coronary events by 51% (p=0.03). Both this and another meta-analysis from Zhang et al including over 12,000 patients in 25 RCTs, provided further reassurance on the safety of PCSK9 inhibition.

Reassurance on efficacy and safety in the largest dataset of heterozygous FH patients treated with a PCSK9 inhibitor (alirocumab) on top of maximally tolerated lipid lowering therapy (ODYSSEY programme).  - Response was sustained over 78 weeks; treatment was well tolerated in the long-term. These results are consistent with those reported in RUTHERFORD-2 with evolocumab (Raal FJ et al 2015). Together, these studies make a strong case for PCSK9 monoclonal antibody therapy in this setting, with lowering of LDL cholesterol to levels previously unobtainable with existing standard-of-care therapy.


What are the main current trials to evaluate the impact of PCSK9 inhibitors?


Randomised outcome trials in progress

Results of clinical outcome trials will be crucial to answer questions on long term safety and efficacy, and to see if these agents are able to reduce cardiovascular morbidity and mortality.  The main trials awaited are listed below:

Evolocumab - FOURIER study: - this compares evolocumab versus statin in 22,500 patients with dyslipidaemia and history of CVD who are high risk of recurrent events.  This study is expected to complete by end of ?2016/2017 – seems to be a query as to when this is but this will be the first one completed.

Alirocumab - ODYSSEY Outcomes long term study: this study compares alirocumab with placebo in 18,000 patients who have well controlled LDL cholesterol  (<1.8mmol/L) who are on maximum lipid modifying therapy with recent acute coronary syndrome.  This study is expected to complete early 2018

Bococizumab - 2 placebo controlled outcome studies

SPIRE 1 Study: 17,000 patients with LDL cholesterol relatively well controlled (1.8-2.6mmol/L) looking at effects of bococizumab in reducing occurrence of major cardiovascular events in high risk patients.  This study should complete by April 2018

SPIRE 2 Study : 9000 patients with dyslipidaemia  despite lipid modifying treatment (>2.6) – this study is expected to complete by Jauary 2018

Further information on PCSK9 can be found at http://www.pcsk9forum.org 


News from 84th European Atherosclerosis Society Congress, 29 May - 1 June 2016, Austria from the PCSK9 Forum 


1. TAUSSIG: Does adding evolocumab reduce cardiovascular events in homozygous FH?

see summary and video where Derick Raal discusses the TAUSSIG study


2. Low LDL-C, PCSK9 and dementia risk:

see summary and video at link below:


3. Changing the message on LDL cholesterol : lifetime exposure is key

summary and video below: