Praluent ® - alirocumab Manufacturer: Sanofi and Regeneron Pharmaceuticals FDA Approval Date: July...

Praluent® - alirocumab

Manufacturer: Sanofi and Regeneron Pharmaceuticals

FDA Approval Date: July 24, 2015


Objectives

• At the end of this presentation participants will be able to:1. Appropriately recommend Praluent®

(alirocumab)

2. Effectively educate patients on the purpose, proper use and potential adverse effects of 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].



• Contraindications:• Serious hypersensitivity reaction

• Black Box warnings: none

• Warning and Precautions:• Hypersensitivity reactions

• Potential for immunogenicity




• 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



Drug Facts

• Pharmacology:• Human monoclonal antibody that inhibits

PCSK9

• PCSK9 is a protease that degrades LDL receptors on hepatocytes.

• LDL receptors clear circulating LDL



Drug Facts

• Pharmacokinetics:

AF = 85%tmax 3-7 days

DVd = 0.04-0.05 L/kg

MExpected to degrade to small peptides and amino acidsDoes not affect CYP450, PGP, or OATP

ET1/2 17-20 days



Drug Interactions

• Drug Interactions – Precipitant Drugs: • Statin reduces half-life of alirocumab to

12 days

• Not clinically significant



Adverse Effects

Praluent Placebo

Allergic Reactions 8.6% 7.8%

Injection Site Reactions 7.2% 5.1%

Influenza 5.7% 4.6%

UTI 4.8% 4.6%

Diarrhea 4.7% 4.4%

Bronchitis 4.3% 4.4%

Myalgia 4.2% 3.4%



Monitoring Parameters

• Efficacy Monitoring:• 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 – accessed 8/11/15• 75 mg or 150 mg injection: $14,600/year



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



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;372:1489-99


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



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



Literature Review

• Baseline CharacteristicsAlirocumab (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

30.2276 (17.8%)

1055 (67.9%)639 (41.1%)542 (34.9%)325 (20.9%)

30.5139 (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



Literature Review

• ResultsAlirocumab

(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% <0.001

LDL<70 in very high risk patients or LDL<100 in

high risk patients80.7% 8.5% -- <0.001

LDL<70 regardless of risk 79.3% 8.0% -- <0.001



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%)

0.710.10

0.0060.83



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



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


References

1. www.praluent.com

2. Praluent [package insert]. Bridgewater, NJ: Sanofi and Regeneron; 2015.

3. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489-99.

4. Pollack A. The New York Times Website. New Drug Sharply Lowers Cholesterol, but it’s Costly. http://www.nytimes.com/2015/07/25/business/us-approves-drug-that-can-sharply-lower-cholesterol-levels.html. Published July 24, 2015. Accessed August 11, 2015.

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