Cardiovascular be an imperative breakthrough for people who


Cardiovascular diseases, such as ischaemic heart disease and
stroke are the primary cause of mortality in recent years. Each year 3.8
million Europeans, mostly in Eastern Europe die from cardiovascular diseases,
due to an increased risk of atherosclerosis, according to the European Health
Network. Key markers of cardiovascular disease include dyslipidemias, such as
hypercholesterolemia, mixed hyperlipidemia and hypertriglyceridemia, which have
a common ground of presenting abnormally high levels of either triglycerides,
low density lipoproteins (LDL) or cholesterol in the blood and subsequently are
disorders of lipid metabolism (Klaus G, 2016) . Historically the treatments of choice
for cardiovascular disease (CVD) are statins, which work to block the liver
enzyme involved in the biosynthesis of cholesterol, known as HMG-CoA reductase.
New investigative strategies are being employed to combat and treat these
diseases, an example of which is the development of Proprotein Convertase
Subtilisin Kexin 9 inhibitors, also known as PCSK9 inhibitors.

These PCSK9 inhibitors are a type of monoclonal antibody
which essentially work to prevent the degradation of LDL receptors in the
lysosomes, as these LDL receptors are crucial in the removal of LDL-C, a type
of harmful cholesterol in the body. These drugs are being investigated as a
potential treatment for hyperlipidemia, which occurs when there is a high level
of LDL, triglycerides and total cholesterol in the blood, and are being
trialled to work in conjunction with the pre-existing treatment of statins, or
as stand-alone drugs, which could be an imperative breakthrough for people who
are resistant to statin treatment, or who are on maximal dose of statin
treatment. In phase 3 clinical trials PCSK9 inhibitors have been shown to give
a 70% reduction of LDL-C levels in the blood (Latimer, et al., 2016). Two PCSK9
inhibitors are currently licenced by the Health Product Regulatory Authority
(HPRA), alirocumab and evolocumab (Yadav, et al., 2016).

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Fat enters the body as chylomicrons, where the trigylycerols
are removed from them before the remains are brought back to the liver, where
the synthesis of very low-density lipoprotein (VLDL) occurs, this VLDL then releases
triglycerols into cells becoming intermediate density lipoprotein (IDL). This
IDL then loses even more triglycerols to become low density lipoproteins (LDL),
which act as a means of packaging cholesterol for transport around the body. Cholesterol
is needed by all body cells, particularly in cell membranes, where it plays a
key role in uncoiling acyl chains of low melting lipids, increasing membrane
fluidity and also for the assistance of bile production in the liver. However,
high levels of cholesterol in the body (dsylipidemia) is associated with the
development of arterial plaques, as an increased inflow and esterification of
cholesterol results in the development of macrophage foam cells, which make up
atherosclerotic plaque. (Yu, et al., 2013).

Development of atherosclerotic plaque starts with irritation
to the arterial wall, such as toxins from cigarette smoke, high levels of LDL-C
and hypertension. This irritation leads to damage of the endothelial layer, known
as atherosclerotic lesions and allows the LDL-C to gather under the affected
area, this accumulated cholesterol then becomes oxidised, resulting in a signal
being sent out to the immune system for monocytes to rush to the area. The
monocytes then convert to macrophages to carry out phagocytosis of the
cholesterol, however the macrophages become over saturated with cholesterol and
cease to function, becoming foam cells and releasing cytokines that signal for
more monocytes to move to the affected area and continuing the cycle.
Eventually the smooth muscle cells migrate from the smooth muscle layer of the
arterial wall to try and cover the thrombogenic plaque by forming a fibrous
cap, while also depositing calcium into the plaque itself. Rupturing of the
atherosclerotic plaque leads to blood clot formation and an increase in the
risk of heart attack and stroke (Burnett, 2004). Therefore, by
decreasing the amount of LDL roaming around the body we reduce the amount of
cholesterol, leading to a decreased chance of atherosclerosis development, and
a decreased chance of cardiovascular disease, which leads to the development of
targeted treatments, such as PCSK9 inhibitors.

These monoclonal antibodies bind selectively to a certain epitope
on PCSK9 which leads to isolation of the protein, where by the peptide
inhibitors work to bind to Proprotein Convertase Subtilisin Kexin 9, a type of
serine protease, as PCSK9 binding stops LDL receptors from being recycled to
the surface of the hepatocyte after internalization, leading to less available
receptors to bind to the LDL-C, and decreasing blood cholesterol clearance (Horton, et al., 2007). With the addition
of the inhibitors, the LDL receptor can return to the surface of the hepatocyte
while the LDL still gets degraded in the lysosome.

was first linked to cholesterol and cardiovascular complications through the
discovery of a gain-of-function mutation of the PCSK9 which caused familial
hypercholesterolemia (Abifadel, et al., 2003). This discovery then
lead to the development of therapeutic agents to target PCSK9, a new class of
lipid lowering drugs, PCSK9 inhibitors, a type of monoclonal antibody (mAbs).
In animal models overexpression of human PCSK9 (p. Ser127Arg and p. Phe216Leu)
in the liver lead to hypercholesterolemia due to a decrease in LDL receptors on
the surface of the hepatocyes, it also caused a two fold increase in total
plasma cholesterol (Maxwell & Breslow, 2004). This discovery seen
as a potential drug target for patients who were on a maximal dose of
lipid-lowering therapy, such as statins, and were still failing to achieve the
guidline LDL cholesterol levels (Hopkins, et al., 2015) PCSK9 was further
confirmed as a drug target when mutations of PCSK9 in subjects with low levels
of LDL-C ( under 58mg/dL) were discovered from the Dallas Heart study and the Atherosclerosis
Risk in Communities study. These mutations (p. Tyr142Ter and p. Cys697Ter) were
associated with a 28% reduction in LDL-C and an 88% reduction in the risk of
developing coronary heart disease (Cohen, et al., 2005)

Two drugs in class were authorised by the Food and Drug
Administration(FDA) and European Medicines Agency (EMA) in 2015, alirocumab
(Sanofi-Aventis/Regeneron) and evolocumab (Amgen) (Everett, et al., 2015) . Both drugs were
approved for the use in conjunction with the maximal tolerated dose of statin
therapy for patients with heterozygous familial hypercholesterolemia or
atherosclerotic cardiovascular disease, while evolocumab was also indicated for
use for patients with homozygous familial hypercholesterolemia (Amgen Inc, 2015)CH1 .

The recommended dosage for subcutaneous injection is 75mg of
alirocumab every two weeks, with an uptitration of 150mg every two weeks if
additional lipid-lowering is required. Evolocumab is also administered through
subcutaneous injection, and is administered bimonthly with a dosage of 140mg,
or monthly with a dosage of 420mg (Amgen Inc, 2015) (Regeneneron Pharmaceuticals &
Sanofi-Aventis, 2015).  In studies from the ODYSSEY programme,
alirocumab, used in conjunction with statins was shown to give a more effective
lowering of LDL-C than ezetimibe, doubling statin dose, or moving to a higher
dose of intense statin treatment (Cannon, et al., 2015) (Bays, et al.,
2015) (Bays, et al.,
2014).  A randomised study of 2341 patients receiving
statins, and with a high risk for cardiovascular events ( ODYSSEY LONGTERM
study) was carried out to measure the efficacy of alirocumab versus placebo (Laufs, et al., 2015). The study found
that after 24 weeks, the LDL-C concentration had lowered by 62%, and in post
analysis, the rate of major adverse cardiovascular events, such as death from
CVD, myocardial infraction(non-fatal), ischemic stroke (fatal and non-fatal)
and unstable angina) was lower in the alirocumab group than with the placebo
group(1.7% vs 3.3%).