The FDA has approved the subcutaneously injected PCSK9 (proprotein convertase subtilisin kexin type 9) inhibitor alirocumab (Praluent – Sanofi/Regeneron) as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-cholesterol (LDL-C). It was not approved for general use in statin-intolerant patients. Alirocumab is the first PCSK9 inhibitor to be approved in the US. Evolocumab (Repatha – Amgen), another PCSK9 inhibitor, was recently approved in Europe and has been recommended for approval for the same indications in the US by an FDA Advisory Committee.
MECHANISM OF ACTION — PCSK9 binds to LDL receptors on hepatocytes, promoting receptor degradation, preventing LDL-C clearance from blood, and increasing serum concentrations of LDL-C. Alirocumab is a human monoclonal antibody that targets PCSK9, prevents it from binding to LDL receptors, and increases hepatic uptake of LDL-C.
NEW GUIDELINES — The American College of Cardiology and the American Heart Association no longer recommend using specific cholesterol targets in the treatment of hyperlipidemia. They now recommend high-intensity statin therapy (e.g., atorvastatin 40-80 mg), which generally results in LDL-C reductions of ≥50%, for patients with clinical atherosclerotic cardiovascular disease.1 The National Lipid Association has recommended use of statins to achieve LDL-C reductions of ≥50% in patients with familial hypercholesterolemia.2
CLINICAL STUDIES — Results of randomized, double-blind clinical trials comparing alirocumab 75-150 mg injected subcutaneously every 2 weeks to oral ezetimibe 10 mg/day or placebo in patients already taking maximally tolerated statin therapy are summarized in Table 2.
A randomized, double-blind trial (LONG TERM) in 2341 patients at high risk for cardiovascular events because of HeFH, established coronary heart disease, or known coronary disease risk factors and with LDL-C levels ≥70 mg/dL despite treatment with maximally tolerated statin therapy compared alirocumab 150 mg with placebo, both injected subcutaneously every 2 weeks for 78 weeks. The mean change in LDL-C at 24 weeks (the primary endpoint) was -61.0% with the active drug and +0.8% with placebo. At 78 weeks of treatment, the mean change was -52.4% with alirocumab and +3.6% with placebo. A post-hoc analysis found that major cardiovascular events occurred in 1.7% of patients treated with alirocumab and in 3.3% of those treated with placebo (p=0.002).3
In an unpublished, randomized, double-blind trial (HIGH FH, summarized in the package insert) in 107 patients with HeFH who had baseline LDL-C levels ≥160 mg/dL despite taking maximally tolerated statin therapy, the mean reduction in LDL-C at 24 weeks (the primary endpoint) was significantly greater with alirocumab 150 mg given every 2 weeks than with placebo (-43% vs -7%).
Two randomized, double-blind trials in a total of 660 high-risk patients taking atorvastatin 20 or 40 mg/day (OPTIONS I) or rosuvastatin 10 or 20 mg/day (OPTIONS II, summarized in the FDA clinical review) found that adding biweekly 75-mg doses of alirocumab reduced LDL-C significantly more than adding ezetimibe, doubling the dose of the statin, or (in OPTIONS I) switching from atorvastatin to a maximally tolerated dose of rosuvastatin.4
ADVERSE EFFECTS — Most clinical trials of alirocumab found no significant differences in adverse events between the active drug and placebo. In the 78-week trial, patients injected with alirocumab were significantly more likely to experience injection-site reactions (5.9% vs 4.2% with placebo) and myalgia (5.4% vs 2.9% with placebo). Neurocognitive events including amnesia, memory impairment, and confusion occurred in some patients with use of alirocumab.1 Hypersensitivity reactions, including some that required hospitalization, have also occurred.
PREGNANCY — Monoclonal antibodies are unlikely to cross the placenta in the first trimester, but may do so subsequently. Animal studies found that alirocumab injections had no adverse effects on the fetus. The drug has not been studied in pregnant women.
DOSAGE AND ADMINISTRATION — The recommended starting dosage of alirocumab is 75 mg injected subcutaneously into the thigh, abdomen, or upper arm every 2 weeks. It can be increased to a maximum of 150 mg if necessary. The injection site should be rotated with each use. If a dose is missed, it should be administered only if the next dose is scheduled to be given at least 7 days later. LDL-C levels should be measured within 4-8 weeks after starting therapy with alirocumab or changing the dose.
Alirocumab is supplied in prefilled pens or glass syringes containing 75 or 150 mg of the drug in 1 mL of solution. Dosage units must be refrigerated, but should be allowed to warm to room temperature for 30-40 minutes before injection. The drug should be discarded if exposed to room-temperature conditions for ≥24 hours, or if the solution is discolored or contains visible particulates.
CONCLUSION — The PCSK9 inhibitor alirocumab (Praluent) given by subcutaneous injection every 2 weeks can further lower LDL-cholesterol levels by 40% or more in patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease already taking maximally tolerated doses of a statin. Limited post-hoc data suggest that it may decrease the incidence of cardiovascular events as well. The long-term efficacy and safety of alirocumab are unknown, and it is expensive.
- NJ Stone et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63:2889.
- JG Robinson et al. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol 2011; 5(3 Suppl):S18.
- JG Robinson et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1489.
- H Bays et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab 2015 June 1 (epub).