What is Alirocumab (Praluent)?

Alirocumab (Praluent): A PCSK9 Inhibitor for LDL Cholesterol Reduction

Alirocumab is a human monoclonal antibody that binds to proprotein convertase subtilisin kexin type 9 (PCSK9), preventing LDLR degradation and significantly increasing LDL receptor availability, thereby lowering LDL cholesterol levels by 50-65% when added to statin therapy. 1, 2

Mechanism of Action

Alirocumab works through a specific mechanism:

• Binds to circulating PCSK9 protein in the bloodstream 1
• Prevents PCSK9 from binding to LDL receptors on hepatocytes 1
• Increases the number and recycling of LDL receptors available on liver cells 1
• Enhances clearance of LDL cholesterol from circulation 1

Clinical Efficacy

Alirocumab demonstrates remarkable efficacy in LDL-C reduction:

• Reduces LDL-C by 45-58% when added to maximally tolerated statin therapy 2
• Allows many patients to achieve LDL-C levels as low as 30-35 mg/dL 2
• Reduces lipoprotein(a) [Lp(a)] by up to 25% 2
• Provides sustained LDL-C reduction over treatment periods of 52-78 weeks 3

FDA-Approved Indications

Alirocumab (Praluent) is approved for:

1. Cardiovascular risk reduction: To reduce risk of heart attack, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease 1

2. Primary hyperlipidemia: To reduce LDL-C in adults with primary hyperlipidemia (including heterozygous familial hypercholesterolemia) as an adjunct to diet, alone or in combination with other lipid-lowering therapies 1

3. Homozygous familial hypercholesterolemia: As an adjunct to other LDL-C-lowering treatments in adults with HoFH who need additional LDL-C lowering 1

4. Pediatric heterozygous familial hypercholesterolemia: As an adjunct to diet and other LDL-C-lowering treatments in children aged 8 years and older with HeFH 1

Dosing and Administration

Alirocumab is administered as a subcutaneous injection:

• Standard dosing: 75 mg subcutaneously every 2 weeks, which can be increased to 150 mg every 2 weeks if additional LDL-C reduction is needed 2
• Alternative dosing: 300 mg every 4 weeks (administered as two 150 mg injections consecutively) 2
• Pediatric dosing (age ≥8 years): Weight-based dosing with 75 mg every 2 weeks for those ≥50 kg and adjusted doses for those <50 kg 1
• Administered in the abdomen, thigh, or upper arm 1

Cardiovascular Outcomes Evidence

The ODYSSEY OUTCOMES trial demonstrated significant cardiovascular benefits:

• Enrolled 18,924 patients (28.8% with diabetes) with recent acute coronary syndrome 2
• Patients received alirocumab or placebo in addition to maximum tolerated statin therapy 2
• Over 2.8 years median follow-up, alirocumab reduced the composite primary endpoint (death from CHD, nonfatal MI, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization) by 15% (HR 0.85,95% CI 0.78-0.93, p<0.001) 2
• Greater absolute risk reduction observed in patients with diabetes (2.3%) compared to those with prediabetes (1.2%) or normoglycemia (1.2%) 2

Safety Profile

Alirocumab demonstrates a favorable safety profile:

• Most common adverse effect is mild injection-site reactions 1, 4
• Other reported adverse effects include myalgia (5.4% vs 2.9% with placebo) 4
• Neurocognitive events (1.2% vs 0.5% with placebo) and ophthalmologic events (2.9% vs 1.9% with placebo) have been reported but are uncommon 4
• No significant increase in muscle-related adverse events compared to placebo 3
• Generally well-tolerated in statin-intolerant patients 2

Target Population

Alirocumab is particularly valuable for:

1. Patients with established atherosclerotic cardiovascular disease not at LDL-C goals despite maximally tolerated statin therapy 2

2. Patients with heterozygous familial hypercholesterolemia requiring additional LDL-C reduction 2

3. Patients with statin intolerance who require LDL-C lowering 2, 5

4. Patients with homozygous familial hypercholesterolemia as an adjunct to other LDL-C-lowering treatments 1

Clinical Considerations

• Store alirocumab in a refrigerator (36°F to 46°F) in the original carton to protect from light 1
• May be kept at room temperature up to 77°F for 30 days 1
• Allow pre-filled pen to warm to room temperature for 30-40 minutes prior to use if refrigerated 1
• Contraindicated in patients with history of hypersensitivity to alirocumab 1
• No dose adjustment needed for patients with mild to moderate renal or hepatic impairment 1

Alirocumab represents a significant advancement in lipid-lowering therapy, particularly for high-risk patients unable to achieve LDL-C targets with conventional therapies or those who cannot tolerate statins.