Evolocumab (Repatha – Amgen), a subcutaneously injected PCSK9 inhibitor, has been approved by the FDA 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 also approved as an adjunct to diet and other LDL-lowering therapies in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C. Evolocumab is the second PCSK9 inhibitor to be approved in the US; alirocumab (Praluent) was approved earlier.1
MECHANISM OF ACTION — PCSK9 (proprotein convertase subtilisin kexin type 9) binding to LDL receptors on hepatocytes promotes receptor degradation, prevents LDL-C clearance from blood, and increases serum concentrations of LDL-C. Evolocumab is a human IgG2 monoclonal antibody that targets PCSK9, prevents it from binding to LDL receptors, and increases hepatic uptake of LDL-C.
A prespecified exploratory analysis of the OSLER-1 and -2 trials found that after one year, the Kaplan-Meier estimated percentages of patients having a cardiovascular event were significantly lower among those receiving evolocumab than those receiving standard treatment alone (0.95% vs 2.18%).2 A more definitive study to evaluate the effect of evolocumab on cardiovascular outcomes (FOURIER) is underway.
ADVERSE EFFECTS — The most common adverse effects reported in clinical trials with evolocumab included nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection-site reactions.
A meta-analysis of 12 randomized, controlled trials found that there were no significant differences in adverse events between evolocumab, ezetimibe, and placebo.7 Neurocognitive events were reported in <1% of patients receiving evolocumab, but more often than in those receiving placebo.
PREGNANCY — Evolocumab has not been studied in pregnant women. Monoclonal antibodies are unlikely to cross the placenta in the first trimester, but may do so subsequently. Animal studies found that evolocumab had no adverse effects on the fetus.
DOSAGE AND ADMINISTRATION — The recommended starting dosage of evolocumab is 140 mg injected subcutaneously once every 2 weeks or 420 mg (three 140-mg injections within 30 minutes) once monthly in patients with HeFH or clinical atherosclerotic cardiovascular disease, or 420 mg once monthly in patients with HoFH. The drug should be injected into the abdomen, thigh, or upper arm; 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 4-8 weeks after starting evolocumab in patients with HoFH.
Evolocumab should be stored in the refrigerator, and warmed to room temperature for at least 30 minutes before injection. It can also be stored at room temperature, but must be used within 30 days.
CONCLUSION — The second FDA-approved PCSK9 inhibitor evolocumab (Repatha) appears to be similar in efficacy and safety to alirocumab (Praluent), but no comparative studies are available. Given by subcutaneous injection every 2 weeks or once monthly, evolocumab can further lower LDL-cholesterol levels by about 60% in patients at high risk for atherosclerotic cardiovascular disease already taking maximal statin therapy. Its effect on cardiovascular outcomes remains to be established. The long-term efficacy and safety of both evolocumab and alirocumab are unknown, and they are expensive.
- Alirocumab (Praluent) to lower LDL-cholesterol. Med Lett Drugs Ther 2015; 57:113.
- MS Sabatine et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1500.
- DJ Blom et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014; 370:1809.
- FJ Raal et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385:331.
- MJ Koren et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014; 63:2531.
- FJ Raal et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385:341.
- XL Zhang et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med 2015; 13:123.