PCSK9 inhibitors are a new class of drugs for lowering LDL cholesterol by inhibiting the PCSK9 protein. They have been shown to reduce LDL levels by 40-72% as monotherapy or in combination with statins. While clinical trials have demonstrated excellent safety and efficacy, their high cost remains a limitation. Current guidelines recommend PCSK9 inhibitors as a second-line option for patients who cannot reach LDL goals despite maximal statin therapy or who are statin intolerant.

1. Dr. Ankur Banik
2nd Year PGT
Dept Of General Medicine
BMCH

2. Background
 PCSK 9 inhibitors are a group of newer drugs against dyslipidemia
primarily having role in reduction of LDL-cholesterol.
 Patients who are eligible for statin therapy but are considered to be
statin intolerant, or having sub optimal response to statins, inhibition of
proprotein convertase subtilism/kexin type9 (PCKS9) has been
proposed as an alternative mechanism of action for lowering LDL
cholesterol.
2

3. Hyperlipidemia and
Atherosclerosis

4. Established Therapies For
Hyperlipidemia
 HMG-CoA Reductase Inhibitors
 Decrease hepatic production of cholesterol via synthesis
blockade
 Increases density of LDL cell surface receptors in the
liver which increases uptake from the plasma
 Most reduction in LDL
 Niacin
 Reduces FFA release from fat tissue and increases
lipoprotein lipase action

5. Established Therapies For
Hyperlipidemia
 Bile Acid Resins
 Bind to bile and prevent its reabsorption, thereby depleting
cholesterol stores
 Used in mild hyperlipidemia with no hypertriglyceridemia
 Fibrates
 Increase lipoprotein lipase activity, uptake of triglycerides
from plasma, and increased synthesis of HDL
 Used mainly for hypertriglyceridemia
 Ezetimibe
 Blocks cholesterol absorption in the intestines causing liver to
absorb LDL from blood stream

6. Why the need for newer drugs ?

7. Limitations of current therapies
 Statins typically reduce LDL-C levels by 30-40% max
depending on the dose and CVE by 30-35% at best even on
optimum dose therapy.
 Efficiency of statins: Doubling the dose of the statin
decreases the LDL level further by only 6%
 Side effects: Muscle weakness, GI intolerance, risk of Type
II diabetes etc.
 Functional limitations of statins as a therapeutic class:
Target level for LDL-C is not met consistently
 Poor adherence to long term regime of dosing
11/22/2016 Pharma Reading: Group No. 6 7

8. 11/22/2016 Pharma Reading: Group No. 6 8

9. New Approaches to LDL Reduction
 Ezetimibe is and will be the only cholesterol
absorption inhibitor in clinical use
 Squalene synthase inhibitor development was
discontinued because of liver toxicity
 The thyroxine receptor agonist Eprotirome study in FH
(Akka) was halted for toxicity in animals
9

10. PCSK 9 Inhibitors: Mechanism of
action
 PCSK9 is a protease that degrades LDL receptors on
hepatocytes.

11. 11
LDL Receptor Function and
Life Cycle
1111

12. 12
PCSK9 & LDL Receptor Expression
12

13. 13
Anti-PCSK9 & LDL Receptor
Expression
13

15. Emerging Therapies
RNAi Therapeutics
1. Genetic targets
11/22/2016 Pharma Reading: Group No. 6 15

16. 11/22/2016 Pharma Reading: Group No. 6 16

17. 17
The PCSK9 protein appears to control the number of low-density lipoprotein receptors

18. PCSK9 Inhibitors
 There are three drugs in this class being developed
 All are monoclonal antibodies for subcutaneous
injection
 Alirocumab
 Currently marketed by Sanofi
 Evolocumab
 marketed by Amgen
 Bococizumab
 Expected release around 2017-2018 by Pfizer

19. PCSK9 Inhibitors: General Facts
 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.
 Given by s.c injections once or twice a month.
 Safety and tolerability profile have so far been
excellent.
 The cost of these drugs are pretty high.

20. Alirocumab (Praluent) – Sanofi7
 Stability at room Temp: 24 hours
 Refrigeration and light protection required
 Pre-filled glass syringes or pre-filled pens
 Administered at either 75 mg or 150 mg subcutaneously q 2
weeks
 Room temp for 30-40 minutes before administration
 Currently FDA approved for addition to maximally
tolerated statin dose for Familial Hypercholesterolemia or
those with clinical ASCVD with sub optimal LDL-Lowering
 $14,600 for 1 year of therapy

21. Clinical Trials For Alirocumab
Trial
Name
Patient
Population
Treatments
* In addition to statin
Result
Odyssey
Options I8
ASCVD and HLD
uncontrolled by
atorvastatin
1)Alirocumab *
2)Ezetimibe *
3)Placebo *
4)Double atorvastatin
dose
5)Switch to
rosuvastatin 40
2 times >
reduction in
LDL
Odyssey
Combo I9
CVD and HLD
uncontrolled by max
tolerated statin dose
1) Alirocumab *
2) Placebo *
45.9 % >
reduction in
LDL
Odyssey
Combo II10
CVD and HLD
uncontrolled by max
tolerated statin dose
1) Alirocumab
2) Ezetimibe
29.8 % >
reduction in
LDL at week
24

22. Clinical Trials For Alirocumab
Trial
Name
Patient
Population
Treatments
* In addition to statin
Result
NCT016444
7411
Moderate CV risk
Not on HLD therapy
1) Alirocumab
2) Ezetimibe
31 % >
reduction in
LDL
Odyssey
Long
Term12
(open
label)
HLD currently on
therapy
In addition to
background therapy:
1) Alirocumab
2) Placebo
61.9 % >
reduction of
LDL
1.6 % < CV
events

23. Clinical Trials For Evolocumab
Trial
Name
Patient
Population
Treatments
* In addition to statin
Result
DESCARTE
S13
Background therapy
of:
Diet
Atorvastatin 10 mg
Atorvastatin 80 mg
Atorvastatin 80 +
Zetia
In addition to
background
therapy:
1) Evolocumab
2) Placebo
Diet: 55.7 % >
reduction Atorv 10:
61.6 % > reduction
Atorv 80: 56.8 % >
reduction
Atorv 80 + zetia:
48.5 % > reduction

24. DESCARTES: UC LDL-C Goal
Achievement
3% 5% 6%
11%
6%
84%
90%
81%
67%
82%
0
10
20
30
40
50
60
70
80
90
100
ProportionofPatients,%
Placebo Evolocumab
Diet Alone Diet +
Atorvastatin
10 mg
Diet +
Atorvastatin
80 mg
Diet +
Atorvastatin
80 mg +
Ezetimibe 10 mg
LDL-C < 70 mg/dL at Week 52
Total

25. DESCARTES: Other Lipids
0
6%
-2
0
2
4
6
3%
(-17 to 25)
-9%
(-26 to 13)
2%
ApoB
Lp(a)
HDL-C
ApoA1
Triglycerides
-42%-50
-40
-30
-20
-10
0
10
-1%
2%
-2
-1
0
1
2
3
-6%
(-21 to 1)
-28%
(-49 to -6)
-30
-25
-20
-15
-10
-5
0
Placebo QM
Evolocumab 420 mg QM
PercentChangefrom
Baseline,Mean(%)
PercentChangefrom
Baseline,Median(%)
PercentChangefrom
Baseline,Median(%)
PercentChangefrom
Baseline,Mean(%)
PercentChangefrom
Baseline,Mean(%)-6
-4
-2
0
2
4
6
-10
-8
Error bars represent standard error
Data in parentheses represent Q1 to Q3

26. Clinical Trials For Evolocumab
Trial
Name
Patient
Population
Treatments
* In addition to
statin
Result
GAUSS II14 Uncontrolled HLD
2 or more statin
intolerances
1) Evolocumab
2) Ezetimibe
20 % >
reduction in
LDL at 12 weeks
MENDEL
II15
< 10 % CV risk and HLD 1) Evolocumab
2) Ezetimibe
3) Placebo
40 % >
reduction than
ezetimibe
50 % >
reduction than
placebo

27. Clinical Trials For Evolocumab
Trial
Name
Patient
Population
Treatments
* In addition to statin
Result
RUTHERF
ORD II16
FH and HLD
uncontrolled by
current therapy
In addition to background
therapy:
1) Evolocumab
2) Placebo
60 % >
reduction in
LDL
LAPLACE
II17
HLD uncontrolled
on current therapy
1) Low intensity
simvastatin,
atorvastatin, or
rosuvastatin
2) High intensity
atorvastatin or
rosuvastatin
1) Evolocumab
2) Ezetimibe
3) Placebo
40 to 50 % >
reduction in
LDL than
ezetimibe
55 to 75 % >
reduction
than
placebo

28. Clinical Trials For Evolocumab
Trial
Name
Patient
Population
Treatmen
ts
* In addition to
statin
Result
TESLA Part
B18
FH uncontrolled on
current therapy
In addition to
background:
1) Evolocuma
b
2) Placebo
30.9% > reduction than
placebo
OSLER and
OSLER II19
(open
label)
HLD receiving
therapy
In addition to
background:
1) Evolocuma
b
2) No change
4.4 % more AEs
0.6 % > neurocognitive
AE
1.23 % less CV events
(HR = 0.47 p<.003)

29.  There are a lot many clinical trials on going with much
larger population and where the focus is on beneficial
affect w.r.t CVE reduction and also on long term safety
and tolerability.
 While the results are still awaiting, the initial findings
have been promising.

30. Current Lipid Treatment Guidelines
Clinical ASCVD
LDL > 190 mg/dL
DM 1 or 2 and age 40-75
ASCVD 10 y risk > 7.5 %
and age 40-75
High intensity statin
unless > 75 years old or
intolerant
High intensity statin
unless intolerant
High intensity statin
unless 10 year ASCVD <
7.5 %
Moderate to high
intensity statin

31. Current Lipid Treatment Guidelines
 No recommendation on LDL targets
 Addition of non-statin drug may be considered if
baseline LDL > 190
 Addition of non-statin drug in suboptimal statin
response or complete statin intolerance is considered a
reasonable option
 Why is there such a preference for statins?
 Why are there no longer LDL targets?

32. The Actual Evidence
 Statin drugs are the only class with actual mortality and
morbidity benefits studied in randomized controlled trials
 No RCT evidence that adjuncts to statin therapy add
clinical benefit
 Actually evidence to the contrary:
 AIM HIGH: niacin added to statin when LDL < 80 mg/dL
provides no benefit23
 ACCORD: adding fenofibrate to statin in patients with DM
provides no benefit22
 Focus Shift from LDL lowering to mortality and morbidity
benefit
 No evidence for target LDL levels in terms of ASCVD event
risk reduction
 High intensity statin therapy ( > 50 % LDL reduction)
provides more clinical benefit than moderate intensity
therapy ( 30-50 % LDL reduction)

33. Recommended Use of PCSK9I’s
 Based on current guidelines, available evidence, and
economic considerations:
 Patients with FH or ASCVD and statin resistance (on max
dose) for additional LDL lowering is a reasonable strategy.
 Discuss with patient costs vs uncertain clinical benefit
 In FH patients to avoid apheresis
 2nd line to addition of ezetimibe for statin intolerant patients
 No evidence to support use of PCSK9I’s as monotherapy or for
arbitrary reduction of statin dose
 In complete statin intolerance, PCSK9I monotherapy should be
considered only after careful risk assessment and patient preference

34. 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 are yet to approve of Evolocumab.
 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.

35. Praluent® - alirocumab
Clinical Application
• Contraindications:
• Serious hypersensitivity reaction
• Black Box warnings: none
• Warning and Precautions:
• Hypersensitivity reactions
• Potential for immunogenicity
Praluent [package insert].

36. Praluent® - alirocumab
Clinical Application
• Pregnancy:
• Category C
• Lactation:
• Unknown if excreted in human breast milk
• Human IgG is present in human milk, but data
suggest breast milk IgG antibodies do not enter infant
circulation in substantial amounts
Praluent [package insert].

37. Praluent® - alirocumab
Drug Interactions
• Drug Interactions – Precipitant Drugs:
• Statin reduces half-life of alirocumab to 12 days
• Not clinically significant
Praluent [package insert].

38. Praluent® - alirocumab
Monitoring Parameters
• Efficacy Monitoring:
• LDL-C within 4 to 8 weeks
Praluent [package insert].

39. Praluent® - alirocumab
Prescription Information
• Dosing:
• Initial dose: 75 mg SC every 2 weeks
• Max dose: 150 mg SC every 2 weeks
• Cost: NY Times – accessed 8/11/15
• 75 mg or 150 mg injection: $14,600/year
Praluent [package insert].

40. Praluent® - alirocumab
Prescription Information
• Administration:
• Warm to room temperature for 30 to 40 min prior to use
• Inject SC into stomach, upper arm, or thighs
• Rotate injection sites
Praluent [package insert].

41. Take Home Messages
 PCSK 9 inhibitors are probably the most promising
amongst all the newer dyslipidemic drugs with the
potential to be the next wonder drug after statins.
 They have already been approved for use in FH, statin
intolerance, failure to achieve LDL-C goals despite
optimal doses of statins in high risk individuals.
 Although the results of a few long term trials are
awaiting, efficacy and safety wise they have shown
great results.
 High cost of therapy remains an issue.

42. THANK YOU