# PCSK9 Inhibitors – a solution for familial hypercholesterolaemia and ischaemic heart disease?

PCSK9 stands for Proprotein Convertase Subtilisin Kexin type 9 and it was first discovered in 2003[1] by Dr. Seidah et al. and it is a 692-amino acid glycoprotein.[2] PCSK9 is secreted by the liver into the circulation[3] and it controls the “number of low-density lipoprotein receptors (LDLR) on the cell surface”[4] and therefore ultimately the amount of LDL cholesterol (LDL-C) in the blood. This is because “PCSK9 can increase levels of LDL cholesterol by decreasing the availability of LDL receptors.”4

Normally a “low-density lipoprotein (LDL) binds to the LDL receptor on the hepatocyte surface”4 where they both then “enter the cell via endocytosis”4 and after that the “LDL receptor dissociates from the LDL and returns to the cell surface”4 in order to bind to more LDL-C particles. Then the “LDL-C is degraded within a lysosome into its protein and lipid components.”4 “The receptor repeats the 10-minute cycle hundreds of times during its 20-hour lifespan”4 lowering the LDL-C levels in the blood. However the process is altered ever so slightly if PCSK9 is present. When PCSK9 is present the PCSK9 protein binds to the LDL receptor along with the LDL molecule and this causes the LDL receptor to be unable to dissociate from the LDL and return to the cell surface of the liver cell. Consequently, it is broken down by the lysosome along with the LDL molecule. This lowers the number of LDL receptors on the cell surface and therefore increases the concentration of LDL-C in the blood.4 In other words the presence of PCSK9 prevents the LDL receptor from escaping the lysosome and so it is also broken down resulting “in decreased numbers of LDLR available on the hepatic cell surface to bind LDL particles and remove them from the circulation and therefore to a subsequent increase in circulating LDL-cholesterol plasma levels.”[5]

However there can be mutations in PCSK9 which can either lead to a gain of function or a loss of function. “Loss of function mutations lead to higher levels of the LDL receptor and lower LDL cholesterol levels.”[6] Basically, a loss of function mutation causes less PCSK9 to be produced. Therefore there are more LDL receptors as they aren’t broken down due to them being able to dissociate from the LDL and return to the hepatocyte (liver cell) surface. This causes a low level of LDL cholesterol to be found in the blood which is “associated with reduced risk of coronary heart disease.”[7] Gain of function mutations cause too much PCSK9 to be produced and “gain of function mutations in PCSK9 reduce LDL receptor levels in the liver, resulting in high levels of LDL cholesterol in the plasma.”Essentially, a gain of function mutation (which results in hypercholesterolemia[8]) increases the effect of PCSK9 expressed making it much more effective as more LDL receptors are degraded – as they can’t dissociate from the LDL-C and so they are broken down – therefore more cholesterol is left in the blood and not removed from circulation. For example “the most powerful PCSK9 gain-of-function mutation, D374Y, is responsible for LDL cholesterol levels of ~10 mmol/L versus ~3 mmol/L in normal subjects.”[9]

Hypercholesterolemia “is a condition characterised by very high levels of cholesterol in the blood”[11] and it is “caused by mutations in the LDLR gene.”[12] These “mutations in the LDLR gene cause an inherited form of high cholesterol called familial hypercholesterolemia”12 which is an autosomal dominant genetic condition meaning if a person has familial hypercholesterolemia there is a 50% chance of passing it onto their child.[13] There are three types of familial hypercholesterolemia (FH): heterozygous FH, compound heterozygous FH and homozygous FH. Heterozygous FH is the most common type and “recent studies indicate that heterozygous FH may affect 1 in 200-250 people.”13 Compound heterozygous FH is where “a child inherits two different types of mutations in FH-causing genes from its parents. This usually leads to a more severe form of FH with higher cholesterol levels.”13 Finally homozygous FH, which is rare, is where “a child inherits the same mutation in FH-causing genes from each parent.”13 Homozygous FH causes such high cholesterol levels that “sudden death from heart attack is common in childhood or adolescence.”13 Globally “there are an estimated 14-34 million people living with FH.”13 It is the “most common genetic condition in the world.”13

An average person has a cholesterol level of about 4.5-6 mmol/l whereas people with heterozygous FH have an approximate LDL-C level of 7.5-12 mmol/l and sufferers of homozygous FH are in the range of 15-30 mmol/l.13

High LDL-C concentrations are dangerous because it can lead to heart disease which “kills more people in the UK than any other disease.”[14] Cholesterol, which is a waxy fat-like substance,  is produced in the body by the liver and can lead to the creation of an atheroma (“a fatty deposit that forms within the wall of an artery.”14) An atheroma restricts blood flow by narrowing the lumen of the artery. This then increases the likelihood of a thrombus forming, which is a blood clot, and this prevents blood flowing through the blood vessel. If a thrombus occurs in a coronary artery (an artery which provides the heart muscle with blood and therefore oxygen and glucose) then the heart muscle will be unable to respire and it would lead to the heart muscle dying and the person would have a heart attack – a myocardial infarction (learn more about Pulse Vascular)

Thus, in order to reduce the number of people with high cholesterol levels and hence lower the number of deaths due to ischaemic heart disease the amount of PCSK9 needs to be lowered or removed entirely. Inhibiting PCSK9 would be the way to do that and a few drugs have been developed recently that are able to inhibit PCSK9.

“There are thought to be around 20 PCSK9 inhibitors in development but the two frontrunners are Amgen’s Evolocumab (Repatha) and Regeneron/Sanofi’s Alirocumab (Praluent.)”[15] Evolocumab and Alicorumab, like other PCSK9 inhibitors, are monoclonal antibodies[16] and “are administered subcutaneously”[17] and they need to be “self-injected every two weeks.”[18]

Recent studies for the “efficacy and safety of Evolocumab”[19] used 4465 patients to further test Evolocumab. These patients received either a 140mg dosage every two weeks or a 420mg monthly dose of Evolocumab and the “patients were followed for a median of 11.1 months.”19 The results showed that “Evolocumab reduced the level of LDL cholesterol by 61% from a median of 120mg per decilitre to 48mg per decilitre.”19 The FDA (Food and Drug Administration) will have made their decision on whether Evolocumab should be approved by August 27th 2015.[20]

Similarly, Alirocumab has been recently tested and The New England Journal of Medicine states that “2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per decilitre (1.8 mmol per litre) or more and were receiving treatment with statins at the maximum tolerated dose”[21] have been involved in the trial. They also said that the “patients were randomly assigned in a 2:1 ratio to receive Alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks.”21 The results showed that “the difference between the Alirocumab and placebo groups in the mean percentage change from baseline in calculated LDL cholesterol level was −62 percentage points; the treatment effect remained consistent over a period of 78 weeks. The Alirocumab group, as compared with the placebo group, had higher rates of injection-site reactions (5.9% vs. 4.2%), myalgia (5.4% vs. 2.9%), neurocognitive events (1.2% vs. 0.5%), and ophthalmologic events (2.9% vs. 1.9%).”21 The verdict for Alirocumab will have been made by the FDA by July 24th 2015.[22]

Overall, both inhibitors approximately lower “LDL cholesterol levels up to 65%.”[23] However, these inhibitors which have been called “one of the biggest developments in a long time in cardiology” by Steve Nissen, the chairman of cardiovascular medicine at Cleveland Clinic[24] would be a very expensive treatment. It is estimated to cost anywhere “from $7,000 to$12,000 per patient annually”[25] and this medication is speculated to “cost the U.S Healthcare system as much as $23 billion a year.”25 On the other hand “analysts predict Evolocumab and Alirocumab could each generate annual sales of over$1 billion by 2020.”[26]

Is the potential to cure ischaemic heart disease, which according to the WHO (World Health Organisation) is the largest cause of death in the world,[27] worth the colossal price tag of these PCSK9 inhibitors when there are current treatments, far cheaper treatments, which work extremely well like statins? Furthermore, the long term effects of these drugs are unknown and so are they really needed?

First of all “even when treated with potent statins, many patients fail to achieve LDL-cholesterol targets and therefore their risk of accelerated atherosclerosis and cardiovascular death remains high.”[28] When 9950 coronary artery disease patients were looked at “only 37% on a statin alone achieved an LDL-cholesterol of <70 mg/dL, and most were on moderate-to-high-potency statins”[29] with <70 mg/dL being the “recommended LDL-cholesterol goal.”29 Furthermore, some patients are unable to take the required high doses of statins necessary to lower their LDL-C levels as a result of side effects[30] most notably muscular symptoms such as myalgia (muscle pain.)[31] Additionally, not only are PCSK9 inhibitors being looked into for reducing the risk of coronary heart disease but “very recent data revealed that the absence of PCSK9 can be protective against melanoma invasion in mouse liver, and that this is due to lower circulating LDL-C.”9 This “opens the door to novel applications of PCSK9 inhibitors/silencers in cancer/metastasis.”9

In conclusion, PCSK9 inhibitors seem to be a very effective treatment for individuals with a high risk of heart disease due to exceedingly high cholesterol levels. They are able to lower the LDL-C concentrations of individuals who aren’t able to reach their safe and recommended levels using statins and they will save countless lives by preventing death from ischaemic heart disease and hypercholesterolemia. Therefore, I believe that PCSK9 inhibitors such as Evolocumab and Alirocumab are effective solutions to familial hypercholesterolemia and ischaemic heart disease.

References:

[1] Abifadel M, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia, Nature Genetics 34, 154-156, (2003).

[14] Glenn Toole, Susan Toole, AQA Biology AS. (Nelson Thornes, Cheltenham, 2008), p.94