PCSK9 Inhibitors: The First of Their Kind

The first of their kind, evolocumab and alirocumab belong to a new class of cholesterol
lowering agents: proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

These human monoclonal antibodies both exert their lipid-lowering effect by binding to PCSK9 and preventing LDL receptors from being degraded in the liver. By inhibiting the destruction of LDL receptors, PCSK9 inhibitors promote the removal of LDL cholesterol (LDL-C) from the circulation, thus lowering levels of LDL-C in the blood.

The labeling for both PCSK9 inhibitors includes indications for patients with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease (ASCVD) who need further LDL-C reductions despite concomitant diet control and statin pharmacotherapy. Evolocumab also has an indication as an adjunct therapy for patients with homozygous familial hypercholesterolemia.

The LDL-C lowering effects observed in clinical trials for both drugs were significant, especially considering these studies evaluated patients on high-dose statin therapy. In a large open-label follow-up of the phase 3 clinical trials evaluating evolocumab, patients treated with the PCSK9 inhibitor in addition to standard lipid-lowering therapy saw a 61% reduction in LDL-C as compared to those treated with standard therapy alone. The combined OSLER-1 and OSLER-2 trials demonstrated the significant LDL-C lowering effect of evolocumab: patients with a median baseline LDL-C level of 120 mg/dL achieved an LDL-C of 48 mg/dL after 12 weeks of therapy.¹ Likewise, alirocumab was evaluated against placebo in a large phase 3 trial in which all patients were given statins +/- other lipid lowering therapy. In the ODYSSEY LONG TERM trial, patients treated with alirocumab experienced a 61% reduction in LDL-C by week 24– reduction in mean LDL-C from 122.7 mg/dL to 48 mg/dL. ²

Evolocumab and alirocumab are both administered via subcutaneous injection. Evolocumab is available as a 140 mg injection given every 2 weeks, or a 420 mg injection given monthly. Patients with homozygous familial hypercholesterolemia should only receive the 420 mg monthly dose.Alirocumab is available as 75 mg or 150 mg injections, which are given every 2 weeks. The 75 mg dose should be used initially, but can be increased to 150 mg if there is an inadequate response after 4 to 6 weeks. Contraindications  include history of hypersensitivity reactions to the respective drugs. Adverse effects of both drugs can include nasopharyngitis, injection site reactions, infection, and musculoskeletal pain.

    Because these drugs are biologics, cost is definitely a concern and recent publications have called into question the cost-effectiveness of PCSK9 therapy at current market prices.³ Additionally, the most recent hyperlipidemia treatment guidelines from the American College of Cardiology and American Heart Association do not include specific recommendations about the use of PCSK9 inhibitors since these drugs were not FDA approved at the time of publication. The guidelines advise against routine use of non-statin therapies due to a lack of strong clinical trial evidence of their effects on cardiovascular outcomes.⁴  Note though that studies of both PCSK-9 inhibitors have seemingly addressed this issue by focusing on clinically meaningful outcomes rather than simply lowering LDL-C.^5,6  Once published, these studies will help to determine the place of PCSK9 inhibitors in therapy moving forward.