This document discusses PCSK9 inhibitors, a new class of drugs for treating hypercholesterolemia. PCSK9 inhibitors work by blocking the PCSK9 protein and preventing degradation of LDL receptors in the liver, thereby significantly reducing LDL cholesterol levels. Clinical trials showed PCSK9 inhibitors reduced LDL-C by 40-72% when added to statin therapy or used alone, lowering cardiovascular event risk. While effective and generally well-tolerated, PCSK9 inhibitors are also very expensive, costing approximately $14,600 per year. Loss of function mutations in the PCSK9 gene, which naturally inhibit the protein, provide lifelong protection from heart disease.

1. PCSK9 inhibitors
PAVOL JOZEF ŠAFÁRIK UNIVERSITY IN KOŠICE FACULTY OF
MEDICINE
Department of internal medicine – new hospital
New hope for hypercholesterolemic patients
Dr. Nasim Badarna 2018
Diploma Thesis
Thesis supervisor: Prof. MUDr. Daniel Pella, PhD.

2. Introduction
 CVD is the #1 cause of death globally
 WHO 2015: An estimated 17.7 million people
died from CVDs in 2015, representing 31% of
all global deaths.
 #1 risk factor is hypercholesterolemia – high
levels of Low density lipoprotien (LDL)

3. Hypercholesterolemia and
Atherosclerosis
 High levels of (LDL) induce the
formation of atherosclerotic plaques
 heart attack and strokes
 Familial(genetic/hereditary):
 Homozygous (HoFH) (rare, 1 in
million)
 Heterozygous (HeFH) (1 in 500).
 Non-familial (rare)

4. Cholesterol management ?
 decrease (LDL-c)  corner stone in the primary and
secondary prevention of cardiovascular disease.

5. Current treatment options
 Statins - HMG-CoA Reductase Inhibitors
 Niacin
 Bile Acid Resins(Cholestyramine, ezetimibe)
 Fibrates

6. Limitations
 Not reaching optimal levels
 Doubling the dose only decreases LDL further
by 6%
 intolerance
 Side effects:
 myopathy, rhabdomyolosis, intolerance to
dosage, risk of Type II diabetes, liver damage,
etc.
 gall stones , impair absorption of fat soluble
vitamins A /D/ E/ K
 cutaneous flushing, warmth and itching

7. We need a new drug !
 Discovery of the PCSK9
 gain of function mutation was responsible for
FH in a French family(Nabil Seidah's group -
2003).
 loss of function mutations were associated
with very low cholesterol levels in a subset of
Afro-Americans(Dallas Heart Study 2006).

8. What is PCSK9?
 Proprotein convertase subtilisin/kexin type 9
 Produced mainly in the liver
 released in the serum and circulates with only
one significant job  regulates serum
cholesterol levels
 causes degradation of the hepatocyte LDL-c
receptors
 leads to increased LDL circulating levels

9. PCSK9 protein
 Binding of the PCSK9 to LDL-receptor complex
 directs the receptor to a lysosome
 Cholesterol is released
 The receptor is degraded – “one and done”
 Maintains serum cholesterol
 In the absence of PCSK9
 the receptor is directed to an endosome
 Cholesterol is released
 The receptor cycles back to the surface to be used
again  Increases effective receptor number which
lowers serum cholesterol

10. PCSK9 protein
Again and again Once and done

11. PCSK9 inhibition
Knocking out this protein
inhibits the PCSK9-
mediated degradation of
LDL-receptor
Leading to dramatically
reduce the amount of
harmful LDL-c circulating
in the bloodstream

12. PCSK9 Inhibitors: General Facts
 monoclonal antibodies against PCSk9 protien
 Reduce LDL-C in the range of 40-72% from
baseline either in combination with statins or as
monotherapy.
 Also reduce apoB and total cholesterol
significantly.
 Modest increase in HDL-C and decrease in TG.
 Safety and tolerability profile have so far been
excellent.

13. What’s in store ?

14. Clinical Trials
alirocumab Evolocumab

15. FOURIER Clinical Trial
 Further cardiovascular OUtcomes Research
with PCSK9 Inhibition in subjects with
Elevated Risk (02.2018)
 Patients with CVD on statin therapy
 Test if addition of evolocumab will reduce CV
events ?
 Efficacy of the drug ?
 Long term safety and tolerability ?

16. FOURIER Clinical Trial

17. FOURIER – results
1. Inhibition of PCSK9 on background of statin therapy lowered LDL-C levels
with evolocumab, as compared with placebo, was 59%
2. Inhibition of PCSK9 reduced the risk of cardiovascular events
3. Evolocumab therapy was safe and well tolerated

18. Phase 3 PCSK9 trials
* Comparison of key design, baseline
characteristics and lipid outcomes from the
completed phase 3 PCSK9 trials

19. Clinical Approval in Europe and
USA
 The European Medicines Agency in July 2015 has
approved Evolocumab as an adjunct to diet in
patients who are unable to reach their
recommended LDL-C goals despite taking optimal
dose of statins.
 They have also approved it of use in homozygous
FH.
 US FDA have approved Alirocumab in patients
with FH, clinical ASCVD in conjunction with
maximally tolerated statin therapy and diet
modification failing to reach LDL-C targets and
statin intolerance.

20. Clinical Application
 Monitoring Parameters
 LDL-C within 4 to 8 weeks
 Prescription Information
 Dosing: Initial dose: 75 mg SC every 2 weeks.
Max dose: 150 mg SC every 2 weeks
 Cost:
 NY Times; injection: $14,600/year
 Application:
 Inject SC
 Contraindications:
 Hypersensitivity reactions
 Immunogenicity
 Black Box warnings: none

21. Take Home Messages
 PCSK 9 inhibitors have the potential to be the
next wonder drug after statins.
 FDA approval for the use in high risk
individuals ,Those at greatest risk are those
who will benefit most.
 High cost of therapy remains an issue.
 Although the results of a few long term trials
are awaiting, the initial findings have been
promising.

23. FH patient on PCSK9 inhibitors:
 “copay program helps, but my first copay
before it kicks in is $1000. Monthly copay is
around $400… But it works. It works very
well. And if I don’t take it, then I have no other
options, besides apheresis”.

24. PCSK9 vs. LDL Apheresis
 LDL apheresis removes unwanted LDL cholesterol
from the blood.
 What is the cost of LDL Apheresis
 Most insurance carriers cover the cost of LDL
apheresis, which is approximately $2500 per
treatment.
 Individuals undergoing LDL apheresis would go to
the Transfusion and Apheresis Service every two
weeks or as indicated. The procedure takes
approximately 2 to 3 hours to complete.
 2500$ *2 = 5000$ per month
 5000$ * 12 = 60,000$ per a YEAR !!!

25. LOF mutation of PCSK9 gene

26. LOF mutation PCSK9 inhibition
Complete lack of PCSK9 Only Inhibition
Independent Dependent on the drug
Life long protection Protection only when on the
drug