PCSK9 inhibitors are new drugs for hypercholesterolemic patients

1. PCSK9 inhibitory
new hope for patients with hypercholesterolemia?
Nasim Badarna
UPJS
kosice, slovakia

2. Structure of the diploma thesis
• Introduction
• Hyperlipidemia and Hypercholesterolemia
• Current treatment
• LDL-receptors
• PCSK9 – new hope ?
• Clinical trial
• Conclusion

3. 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 .

4. 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.

5. 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.

6. • 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

7. LDLHDL
• 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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

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

14. 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.

15. 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

16. • 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.

17. Eligibility
Criteria
Inclusion Criteria:
Subjects with familial hypercholesterolemia:
•Aged between 18-65 years
•Carrier of a mutation in the LDL receptor gene
Exclusion 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

18. 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

19. 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…

21. • http://circ.ahajournals.org/content/12
6/20/2408.short
• http://circ.ahajournals.org/content/12
6/20/2408.short

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