What to Know About First Approved PCSK9 Inhibitor

Pharmacists should be aware that the FDA recently approved the first cholesterol-lowering proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor antibodies.

First-in-class alirocumab (Praluent) from Sanofi and Regeneron Pharmaceuticals got the nod on July 24, 2015, while Amgen’s evolocumab (Repatha) was approved in August.

Alirocumab is a subcutaneous injection indicated for use in addition to diet and maximally tolerated statin therapy in adult patients with heterozygous familial hypercholesterolemia (HeFH) or those with clinical atherosclerotic cardiovascular disease such as heart attack or stroke who require additional lowering of low-density lipoprotein (LDL) cholesterol.

Importantly, the effect of alirocumab on cardiovascular morbidity and mortality has not been determined.

Alirocumab mechanism of action

Alirocumab works by inhibiting the activity of proprotein convertase subtilisin/kexin type 9, a protein in the blood.

Normally, PCSK9 inhibits the function of LDL receptors (LDLRs) on the surface of liver cells, limiting the ability of LDLRs to capture and sequester LDL cholesterol from the blood. As alirocumab inhibits PCSK9 activity, more LDLRs remain on the surface of liver cells, and with more LDLRs present, more LDL cholesterol is captured from the blood and sequestered in the liver.

By lowering LDL cholesterol levels, alirocumab may reduce cardiovascular risk, particularly in statin-intolerant patients or those who have not achieved a 50% or greater reduction in LDL cholesterol with existing therapies alone.

Alirocumab dosage and administration

Alirocumab is supplied in single-dose prefilled pens and syringes. The recommended starting dose is 75 mg administered subcutaneously every 2 weeks. If LDL cholesterol response is inadequate, the dosage may be increased to 150 mg administered every 2 weeks.

LDL cholesterol should be measured within 4 to 8 weeks of initiating or titrating alirocumab treatment to assess response. Steady-state LDL cholesterol levels are generally achieved within 4 weeks of treatment initiation or dosage adjustment.

Alirocumab pharmacokinetics

Pharmacokinetic analysis of alirocumab indicates a half-life of 17 to 20 days at steady-state levels. When alirocumab is used with statins, however, its half-life is shortened to 12 days.

This shortened elimination half-life may occur because statins increase PCSK9 production, resulting in increased alirocumab clearance as it binds with circulating PCSK9 proteins.

There are no data on the disposition of alirocumab in patients with severe renal or hepatic impairment due to exclusion of these patients from clinical studies. However, pharmacokinetic parameters were not affected by race, sex, or mild to moderate hepatic or renal impairment.

Alirocumab clinical studies

Alirocumab has been studied in 3188 patients with hypercholesterolemia across 10 double-bind phase 3 studies of 6 to 24 months’ duration.

Half of these studies compared alirocumab with placebo, while the other half compared alirocumab with ezetimibe. Three studies included patients with HeFH, a genetic condition that predisposes patients to high cholesterol levels, and 1 study was limited to statin-intolerant patients. Nearly one-third (30%) of patients receiving alirocumab had diabetes mellitus.

Across all 10 studies, use of alirocumab resulted in:

· A 45.6% to 48.9% reduction in LDL cholesterol levels over the first 24 weeks of therapy.

· LDL cholesterol level reductions averaging 60.4% in patients receiving intensified dosing of alirocumab (150 mg every 2 weeks).

· A 50% or greater reduction in LDL cholesterol levels over 24 weeks of therapy in 54.6% to 75.7% of users, depending on the clinical trial population.

Alirocumab warnings and precautions

Common adverse events with alirocumab that occurred more frequently in patients taking placebo included injection site reactions and pruritus. In patients receiving alirocumab and ezetimibe, common adverse events included myalgia (6.7%), upper respiratory tract infection (5.9%), and nasopharyngitis (5.4%).

Most adverse events were transient, of mild intensity, and did not result in treatment discontinuation.

Local injection site reactions were the most common adverse event resulting in treatment discontinuation, with 0.2% of patients receiving alirocumab discontinuing due to local reactions, compared with 0.3% of those in control groups.

Hypersensitivity, hypersensitivity vasculitis, and nummular eczema have all been observed in association with alirocumab exposure. Although many of these hypersensitivity events led to discontinuation of therapy, all recorded cases resolved after alirocumab discontinuation and/or a short course of corticosteroid therapy.

Researchers did not identify any increased risk for neurocognitive events, with the exception of an imbalance between the treatment and control groups in a 78-week study. Neurocognitive events occurred in a total of 29 patients taking alirocumab across all clinical trials.

Antidrug antibodies appeared in 4.8% of patients receiving alirocumab compared with 0.6% of patients receiving control medications or placebo, whereas drug-neutralizing antibodies appeared in 1.2% of patients receiving alirocumab.

Importantly, drug-neutralizing antibodies usually appeared on a single test, and not on subsequent ones. Patients with 2 or more blood samples containing drug-neutralizing antibodies comprised just 0.3% of patients.

In patients with diabetes mellitus, treatment with alirocumab did not result in clinically meaningful changes in glycemic control.

Concerning reproductive impairment, there were no adverse effects on surrogate markers of fertility in a chronic toxicology study in sexually mature monkeys, and there were no adverse alirocumab-related anatomic pathology or histopathology findings in reproductive tissues in rat or monkey toxicology studies.