1. Praluent® - alirocumab
Manufacturer: Sanofi and Regeneron Pharmaceuticals
FDA Approval Date: July 24, 2015

2. Praluent® - alirocumab Objectives
At the end of this presentation participants will be able to:
Appropriately recommend Praluent® (alirocumab)
Effectively educate patients on the purpose, proper use and potential adverse effects of Praluent® (alirocumab)

3. Praluent® - alirocumab Clinical Application
Indications:
Treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease
Place in therapy:
Those who need additional LDL lowering despite maximally tolerated statin
Praluent [package insert].

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

5. 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].

6. Praluent® - alirocumab Drug Facts
Pharmacology:
Human monoclonal antibody that inhibits PCSK9
PCSK9 is a protease that degrades LDL receptors on hepatocytes.
LDL receptors clear circulating LDL
PCSK9 = proprotein convertase subtilisin kexin 9
Alirocumab is a human monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9). PCSK9 binds to the low-density lipoprotein receptors (LDLR) on the surface of hepatocytes to promote LDLR degradation within the liver. LDLR is the primary receptor that clears circulating LDL, therefore the decrease in LDLR levels by PCSK9 results in higher blood levels of LDL-C. By inhibiting the binding of PCSK9 to LDLR, alirocumab increases the number of LDLRs available to clear LDL, thereby lowering LDL-C levels.
Praluent [package insert].

7. Praluent® - alirocumab Drug Facts
Pharmacokinetics: A
F = 85%
tmax 3-7 days D
Vd = L/kg M
Expected to degrade to small peptides and amino acids
Does not affect CYP450, PGP, or OATP E
T1/ days
Praluent [package insert].

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

9. Praluent® - alirocumab Adverse Effects
Placebo
Allergic Reactions
8.6%
7.8%
Injection Site Reactions
7.2%
5.1%
Influenza
5.7%
4.6%
UTI
4.8%
Diarrhea
4.7%
4.4%
Bronchitis
4.3%
Myalgia
4.2%
3.4%
Praluent [package insert].

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

11. 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].

12. 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].

13. Praluent® - alirocumab Literature Review
ODYSSEY LONG TERM
Purpose: to obtain longer-term data n safety and efficacy of alirocumab
Design: randomized, double blind, phase 3 trial
320 sites in 27 countries
Robinson JG, et al. N Engl J Med. 2015;372:

14. Praluent® - alirocumab Literature Review
Inclusion Criteria
Exclusion Criteria
Age >18 years
Heterozygous familial hypercholesterolemia
Established CHD or CHD risk equivalent
LDL-C >70 mg/dl
High dose statin therapy or maximum tolerated dose for >4 weeks before screening
LDL-C <70 mg/dl
Statin other than simvastatin, atorvastatin, or rosuvastatin
Homozygous familial hypercholesterolemia
CHF Class III or IV
BP >180/110
Robinson JG, et al. N Engl J Med. 2015;372:

15. Praluent® - alirocumab Literature Review
Intervention: alirocumab 150 mg q2 weeks vs. placebo
Primary endpoint: percent change in LDL-C from baseline to week 24
Secondary endpoint: percent change in other lipoprotein variables
Post-hoc analysis: rate of adjudicated major adverse CV events between groups
Randomly assigned in a 2:1 ratio
78 weeks
Post hoc analysis: composite endpoint of death from CHD, nonfatal MI, fatal or nonfatal stroke, unstable angina requiring hospitalization  primary endpoint of ongoing study
Robinson JG, et al. N Engl J Med. 2015;372:

16. Praluent® - alirocumab Literature Review
Baseline Characteristics
Alirocumab (N=1553)
Placebo (N=788)
Age
60.4
60.6
Male
983 (63.3%)
474 (60.2%)
White
1441 (92.8%)
730 (92.6%)
CV history and risk factors:
BMI
Heterozygous FH
CHD
CHD risk equivalent
Type 2 DM
Current smoker
30.2
276 (17.8%)
1055 (67.9%)
639 (41.1%)
542 (34.9%)
325 (20.9%)
30.5
139 (17.6%)
552 (70.1%)
323 (41.0%)
267 (33.9%)
159 (20.2%)
Lipid-modifying medications:
Any statin
High-dose statin
1552 (>99.9%)
727 (46.8%)
787 (99.9%)
368 (46.7%)
LDL-C
122.7
121.9
Triglycerides
132.0
135.0
HDL-C
49.8
50.0
Robinson JG, et al. N Engl J Med. 2015;372:

17. Praluent® - alirocumab Literature Review
Results
Alirocumab
(N=1530)
Placebo (N=780)
LS Mean Difference
P-value
Baseline LDL-C
122.8
122.0 --
Absolute level at wk 24
48.3
118.9
Percent change from baseline to wk 24
-61.0%
0.8%
-61.9%
<0.001
Percent change from baseline to wk 78
-52.4%
3.6%
-56.0%
LDL<70 in very high risk patients or LDL<100 in high risk patients
80.7%
8.5%
LDL<70 regardless of risk
79.3%
8.0%
Difference between alirocumab and placebo groups in percentage change in LDL from baseline to week 24 was similar in patients with heterozygous FH and those without.
Robinson JG, et al. N Engl J Med. 2015;372:

18. Praluent® - alirocumab Literature Review
Safety endpoints
Alirocumab
(N=1550)
Placebo (N=788)
P-value
Adjudicated major adverse CV events in post hoc analysis
27 (1.7%)
26 (3.3%)
0.02
Death from CHD
4 (0.3%)
7 (0.9%)
0.26
Nonfatal MI
14 (0.9%)
18 (2.3%)
0.01
Fatal or nonfatal ischemic stroke
9 (0.6%)
2 (0.3%)
0.35
Adverse effects:
General allergic reaction
Injection site reaction
Myalgia
Neurologic event
156 (10.1%)
91 (5.9%)
84 (5.4%)
65 (4.2%)
75 (9.5%)
33 (4.2%)
23 (2.9%)
35 (4.4%)
0.71
0.10
0.006
0.83
Robinson JG, et al. N Engl J Med. 2015;372:

19. Praluent® - alirocumab Literature Review
Conclusions:
Alirocumab significantly reduces LDL-C when added to maximum tolerated statin therapy in patients with heterozygous familial hypecholesterolemia and patients with CHD or CHD risk equivalent
In the post-hoc analysis, there was evidence of reduction in the rate of CV events with alirocumab
Robinson JG, et al. N Engl J Med. 2015;372:

20. Praluent® - alirocumab Summary
Praluent® (alirocumab) is the first-in-class PCSK9 inhibitor that reduces LDL-C
Indicated for the treatment of adults with heterozygous familial hypercholesterolemia or clinical ASCVD, who require additional LDL-C lowering despite diet and maximally tolerated statin therapy
Dose is 75 or 150 mg every 2 weeks given as a SC injection
The most common AEs observed include hypersensitivity reactions
LDL-C should be monitored within 4-8 weeks

21. Praluent® - alirocumab References
Praluent [package insert]. Bridgewater, NJ: Sanofi and Regeneron; 2015.
Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:
Pollack A. The New York Times Website. New Drug Sharply Lowers Cholesterol, but it’s Costly. approves-drug-that-can-sharply-lower-cholesterol- levels.html. Published July 24, Accessed August 11, 2015.