General Information

Praluent (alirocumab) is a PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor antibody.

Praluent is specifically indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-cholesterol (LDL-C). Praluent is also indicated to reduce the risk of heart attack, stroke and unstable angina requiring hospitalization in adults with established cardiovascular (CV) disease.

Mechanism of Action

Praluent (alirocumab) is a human monoclonal antibody that binds to 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.

Side Effects

Adverse effects associated with the use of Praluent may include, but are not limited to, the following:

• Nasopharyngitis
• Injection site reactions
• Influenza

Dosing/Administration

Praluent is supplied as an injection for subcutaneous use. The recommended starting dose for Praluent is 75 mg administered subcutaneously once every two weeks because most patients achieve sufficient LDL-C reduction with this dosage. If the LDL-C response is inadequate, the dosage may be increased to the maximum dosage of 150 mg administered every two weeks.

Clinical Trial Results

FDA Approval

The FDA approval of Praluent was based on five double-blind placebo-controlled trials that enrolled 3,499 patients; 36 percent were patients with heterozygous familial hypercholesterolemia (HeFH) and 54 percent were non-FH patients who had clinical atherosclerotic cardiovascular disease. Three of the five trials were conducted exclusively in patients with HeFH. All patients were receiving a maximally tolerated dose of a statin, with or without other lipid-modifying therapies. All trials were at least 52 weeks in duration with the primary efficacy end point measured at week 24 (mean percentage change in LDL-C from baseline). Three studies used an initial dose of 75 mg every two weeks (Q2W) followed by criteria-based uptitration to 150 mg Q2W at week 12 for patients who did not achieve their predefined target LDL-C at week 8. The majority of patients (57 percent to 83 percent) who were treated for at least 12 weeks did not require up-titration. Two studies used a 150-mg Q2W dose. 

Study 1 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 1,553 patients to Praluent 150 mg Q2W and 788 patients to placebo. Overall, 69 percent were non-FH patients with clinical atherosclerotic cardiovascular disease and 18 percent had HeFH. The average LDL-C at baseline was 122 mg/dL. At week 24, the treatment difference between Praluent and placebo in mean LDL-C percent change was -58 percent (p-value: ˂0.0001). 

Study 2 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 209 patients to Praluent and 107 to placebo. Overall, 84 percent had clinical atherosclerotic cardiovascular disease. Mean baseline LDL-C was 102 mg/dL. At week 12, the mean percentage change from baseline in LDL-C was -45 percent with Praluent compared to 1 percent with placebo, and the treatment difference between Praluent 75mg Q2W and placebo in mean LDL-C percent change was -46 percent. At week 12, if additional LDL-C lowering was required based on prespecified LDL-C criteria, Praluent was up-titrated to 150 mg Q2W for the remainder of the trial. At week 24, the mean percentage change from baseline in LDL-C was -44 percent with Praluent and -2 percent with placebo, and the treatment difference between Praluent and placebo in mean LDL-C percentage change was -43 percent (p-value: ˂0.0001). The dose was up-titrated to 150 mg Q2W in 32 (17 percent) of 191 patients treated with Praluent for at least 12 weeks. 

Studies 3 and 4 were multicenter, double-blind, placebo-controlled trials that, combined, randomly assigned 490 patients to Praluent and 245 to placebo. The trials were similar with regard to both design and eligibility criteria. All patients had HeFH, were taking a maximally tolerated dose of statin with or without other lipid-modifying therapy and required additional LDL-C reduction. Overall, 45 percent of these patients with HeFH also had clinical atherosclerotic cardiovascular disease. The average LDL-C at baseline was 141 mg/dL. At week 12, the treatment difference between Praluent 75 mg Q2W and placebo in mean LDL-C percent change was -48 percent. At week 12, if additional LDL-C lowering was required based on prespecified LDL-C criteria, Praluent was up-titrated to 150 mg Q2W for the remainder of the trials. At week 24, the mean treatment difference between Praluent and placebo in mean LDL-C percentage change from baseline was -54 percent (p-value: ˂0.0001). The dose was up-titrated to 150 mg Q2W in 196 (42 percent) of 469 patients treated with Praluent for at least 12 weeks. The LDL-C-lowering effect was sustained to week 52. 

Study 5 was a multicenter, double-blind, placebo-controlled trial that randomly assigned 72 patients to Praluent 150 mg Q2W and 35 patients to placebo. Patients had HeFH with a baseline LDL-C ≥160 mg/dL while taking a maximally tolerated dose of statin with or without other lipid-modifying therapy. Overall, 50 percent had clinical atherosclerotic cardiovascular disease. The average LDL-C at baseline was 198 mg/dL. At week 24, the mean percentage change from baseline in LDL-C was -43 percent with Praluent  and -7 percent with placebo, and the treatment difference between Praluent  and placebo in mean LDL-C percentage change was -36 percent (p-value: ˂0.0001).

The FDA approval of Praluent to reduce the risk of heart attack, stroke and unstable angina requiring hospitalization in adults with established cardiovascular (CV) disease was based on Odyssey Outcomes, assessing the effect of adding Praluent to maximally-tolerated statins on CV outcomes in 18,924 patients who had an acute coronary syndrome (ACS) within a year of enrolling in the trial. Patients who received Praluent in the trial experienced:

• A 15 percent reduced risk for major CV events. The primary end point included time to first heart attack, stroke, death from coronary heart disease (CHD), or unstable angina requiring hospitalization 
• A 27 percent reduced risk of stroke, 14 percent reduced risk of non-fatal heart attack and 39 percent reduced risk of unstable angina requiring hospitalization.
• A 15 percent reduced risk of death from any cause (also called all-cause mortality) was also observed.