This document discusses PCSK9 inhibitors, which are a new class of drugs for treating hyperlipidemia. It describes three PCSK9 inhibitors in development (alirocumab, evolocumab, bococizumab) and summarizes results from clinical trials of alirocumab and evolocumab. When added to statin therapy, these PCSK9 inhibitors provided additional LDL cholesterol reductions of 30-60% compared to placebo or ezetimibe alone in many trials. Larger outcomes trials are still ongoing to determine if PCSK9 inhibitors can also reduce cardiovascular events when added to statins. Current lipid guidelines prefer high-intensity statins but allow adding non-statin drugs like

1. PCSK9 Inhibitors

2. Hyperlipidemia and Atherosclerosis1

3. Established Therapies For
Hyperlipidemia
 HMG-CoA Reductase Inhibitors2
 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
 Ezetimibe3
 Blocks cholesterol absorption in the intestines causing liver to absorb LDL from
blood stream
 Niacin4
 Reduces FFA release from fat tissue and increases lipoprotein lipase action

4. Established Therapies For
Hyperlipidemia
 Bile Acid Resins5
 Bind to bile and prevent its reabsorption, thereby depleting cholesterol stores
 Used in mild hyperlipidemia with no hypertriglyceridemia
 Fibrates6
 Increase lipoprotein lipase activity, uptake of triglycerides from plasma, and
increased synthesis of HDL
 Used mainly for hypertriglyceridemia

5. PCSK9 Inhibitors7

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

7. 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 (prescribing info)
 $14,600 for 1 year of therapy

8. Clinical Trials For Alirocumab With
Results
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

9. Clinical Trials For Alirocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
NCT016444741
1
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

10. Clinical Trials For Alirocumab Awaiting
Results
Trial
Name
Patient Population Treatments
* In addition to statin
Endpoint
Odyssey FH II FH and statin treatment failure 1) Alirocumab *
2) Placebo *
% Δ in LDL
at week 24
Odyssey
Options II
HLD currently on rosuvastatin 1) Alirocumab
2) Ezetemibe
3) Placebo
% Δ
in LDL at
week 24
Odyssey High
FH
FH patients receiving therapy In addition to
background therapy:
1) Alirocumab
2) Placebo
% Δ
in LDL at
week 24
Efficacy and
Safety in CHD
and FH
High CV risk or FH uncontrolled
on current therapy
In addition to
background therapy:
1) Alirocumab
2) Placebo
% Δ
in LDL at
week 24

11. Clinical Trials For Alirocumab Awaiting
Results
Trial
Name
Patient Population Treatments
* In addition to statin
Result
Odyssey
Choice II
HLD uncontrolled by non-statin
therapy
In addition to background
therapy:
1) Alirocumab
2) Placebo
% change
in LDL at
week 24
Odyssey
MONO
Non FH HLD 1) Alirocumab
2) Placebo
% change
in LDL at
week 24
Odyssey
Choice I
Low, medium, high CV risk
With or without statin therapy
In addition to background
therapy:
1) Alirocumab
2) Placebo
% change
in LDL at
week 24

12. Clinical Trials For Alirocumab Awaiting
Results
Trial
Name
Patient Population Treatments
* In addition to statin
Result
Odyssey
Alternative
HLD and low, moderate, or
high CV risk
1) Alirocumab
2) Ezetimibe
3) Atorvastatin
4) Placebo
% change in LDL at
24 weeks
Odyssey
Escape
FH receiving apheresis 1) Alirocumab
2) Placebo
apheresis
requirements
normalized to
baseline schedule
Odyssey
Outcomes
Post MI taking max tolerated
rosuvastatin or atorvastatin
dose
1) Alirocumab *
2) Standard MI therapy
Time to 1st event
(CV death, MI, hosp
for UA, or ischemic
stroke)

13. Clinical Trials For Evolocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
DESCARTES13 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

14. Clinical Trials For Evolocumab With
Results
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

15. Clinical Trials For Evolocumab With
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
RUTHERFORD
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

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

17. Clinical Trials For Evolocumab Awaiting
Results
Trial Name Patient Population Treatments
* In addition to statin
Endpoint
NCT01953328 Japanese
High CV risk and HLD
1) Low intensity atorvastatin
2) High intensity atorvastatin
1) Evolocumab
2) Placebo
% change in
LDL at week 10
and 12
NCT02304484
(open label)
CVD and HLD In addition to background:
1) Evolocumab
2) No change
2 year safety
endpoints
HAUSER-RCT 10-17 years old
FH uncontrolled by statin
1) Evolocumab *
2) Placebo *
% change in
LDL at week 24

18. Clinical Trials For Evolocumab Awaiting
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
FLOREY Moderate to low CV risk
No current therapy
1) Evolocumab
2) Evolocumab + atorvastatin
3) Placebo
% change in LDL
fractional
catabolic rate at
60 days
NCT01984424 Statin intolerance history Atorvastatin run in:
1) Evolocumab *
2) Ezetimibe *
% change in LDL
at 22 and 24
weeks
GLAGOV CVD and currently on
therapy
In addition to background:
1) Evolocumab
2) Placebo
Nominal change
in % artheroma
volume at week
78

19. Clinical Trials For Evolocumab Awaiting
Results
Trial Name Patient Population Treatments
* In addition to statin
Result
EBBINGHAUS CVD and non FH HLD
Extension of FOURIER
FOURIER study patients on
either statin plus evolocumab
or statin plus placebo
Average change
in spatial
working
memory
FOURIER CVD and non FH HLD 1) Evolocumab + statin
2) Statin
Time to 1st
event

20. Current Lipid Treatment Guidelines20
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

21. Current Lipid Treatment Guidelines20
 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?

22. 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)27

23. IMPROVE-IT21
High Risk Patients within 10
days of ACS
Placebo + Simvastatin 40 mg
Ezetimibe 10 mg +
Simvasatatin 40 mg
Time to first event
(CV death, MI, hospitalization for UA, coronary artery revascularization > 30 days post
randomization, or stroke)

24. Implications of IMPROVE-IT21
 Ezetimibe + moderate intensity simvastatin produces modest ASCVD event
rate reduction
 6.4 % RRR (HR 0.936 p < 0.016)
 Evidence that lowering LDL, not statin intensity, should be the goal
 Further reduction of LDL beyond statins should be implemented
 So can we expect PCSK9 inhibitors to show real clinical benefit based on
the results of IMPROVE-IT?

25. Problems With IMPROVE-IT
 Ezetimibe also reduced expression of thrombomodulin, platelet
endothelial cell adhesion molecule, and vitronectin receptor24
 Also improved multiple indices of platelet reactivity24
 Conclusion that LDL reduction mediates ezetimibe ASCVD risk reduction is
confounded
 No evidence that these results extend to other lipid lowering agents
 No evidence that addition to high intensity statin is also beneficial

26. How Much Did We IMPROVE-IT?
 Addition of ezetimibe reduced the risk of any endpoint, but did not reduce
deaths.
 Results were mainly driven by reduction in MI and stroke rates
 The Average cost of MI in medicare patients is about 20,000 dollars (30 day
total treatment)25
 The average cost of a stroke over a patient lifetime has been estimated as
about 100,000 dollars (all subtypes averaged)26
 Assuming these are the only two events that occurred (probably most
expensive scenario):
 in one year, 1 in 350 patients (NNT) treated with simvastatin but no Zetia would cost
an average of 60,000 dollars to healthcare
 In contrast, treating 350 patients for a year with Zetia would cost ($250/30
days * 12 month/year * 350 patients) about 1 million dollars. (good Rx)
 This is a very expensive price for society to pay for such a small benefit

27. IMPROVE-IT and PCSK9 Inhibitors
 IMPROVE-IT does not necessarily ensure the clinical benefit of PCSK9I’s
 PCSK9 inhibitors cost $12,000 more per patient-year
 Given previous assumptions, for PCSK9 inhibitors to be cost neutral the NNT
would need to be 4 (compared to 350 for zetia)
 Even assuming $500,000/event cost, the NNT would need to be 33
 Increasing statin intensity has a NNT/year of about 50, so PCSK9I’s achieving
an NNT of 33 is unlikely6
 Health plan reactions will probably include:
 Negotiating lower prices from manufacturers in exchange for exclusivity
 Limiting beneficiary access through high coinsurance
 raising premiums for all members
 Involved prior auth process including proof of adequate exercise, adequate trial of
two statins, adequate trial of moderate statin with zetia, laboratory tested statin
intolerance.

28. 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

29. Sources
 Clinicaltrials.gov
 All trials with no published data
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