Evinacumab

Introduction

Evinacumab is a fully human, recombinant monoclonal antibody (mAb) that is an inhibitor of angiopoietin-like protein 3 (ANGPTL3). The Food and Drug Administration (FDA) approved evinacumab for the treatment of patients with homozygous familial hypercholesterolemia (HoFH) in February 2021. Patients with HoFH require intensive intermediate density lipoprotein cholesterol (LDL-C)-lowering, but since HoFH is very rare, the range of available treatments is restricted. Low-density lipoprotein (LDL) apheresis is often required. Pharmacologically, statins are an important option, but up to 98% of patients with HoFH will not meet their LDL-C reduction goals on statins alone; other common nonstatins are not as efficacious in patients with HoFH, with PCSK9 inhibitors showing a reduced LDL-C-lowering efficacy (25-30%) in this patient group. Pharmacological agents approved specifically for HoFH includes lomitapide. Thus, the approval of evinacumab fills an important therapeutic gap, although with an average annual wholesale cost of $450,000, affordability is a concern.

Appropriate Uses

The FDA has approved evinacumab as an adjunct to other LDL-C-lowering therapies for the treatment of adult and pediatric patients, 12 years of age and older, with HoFH. The package insert for evinacumab (trade name Evkeeza) lists two limitations of use:

• The safety and effectiveness of evinacumab have not been established in patients with other causes of hypercholesterolemia, including those with heterozygous FH (HeFH)
• The effects of evinacumab on cardiovascular morbidity and mortality have not been determined.

Evinacumab was approved after the 2018 multi-society cholesterol guideline was published, and therefore that guideline contains no recommendations on its use. The 2022 ACC Expert Consensus Decision Pathway on the use of nonstatins recommends that evinacumab be considered in the following cases:

• Patients with HoFH, baseline LDL-C ≥190 mg/dL and very high risk atherosclerotic cardiovascular disease (ASCVD) (secondary prevention) who do not achieve ≥50% reduction in LDL-C levels and an absolute LDL-C level of <55 mg/dL on maximally-tolerated statin therapy
• Patients with HoFH, baseline LDL-C ≥190 mg/dL and no clinical ASCVD (primary prevention) who do not achieve ≥50% reduction in LDL-C levels and an absolute LDL-C level of <100 mg/dL on maximally-tolerated statin therapy
• Selected patients with HoFH and baseline LDL-C ≥190 mg/dL or very high risk ASCVD who have statin-associated side effects, after ezetimibe and/or PCSK9 monoclonal antibodies (first-line therapy) and bempedoic acid or inclisiran (second-line therapy) have been tried.

Mechanism of Action

Evinacumab is an inhibitor of ANGPTL3 (Figure 30-1), an enzyme synthesized in and secreted by the liver, which belongs to a family of lipoprotein metabolism regulators. ANGPTL3 inhibits lipoprotein lipase (LPL) and endothelial lipase (EL). Through a mechanism that remains to be fully elucidated, inhibition of ANGPTL3 and the corresponding increase in LPL and EL activity results in a reduction of LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglyceride levels. The mechanism likely involves promotion of very low-density lipoprotein (VLDL) processing and decreased production of LDL particles; data from preclinical studies in mice genetically deficient for both the LDL-C receptor pathway and apoE-mediated LDL clearance suggest that evinacumab does not increase LDL clearance.

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LDL-C Lowering Efficacy

Patients with Homozygous Familial Hypercholesterolemia

The efficacy of evinacumab for the treatment of patients with HoFH was assessed in ELIPSE HoFH, a 24-week, double-blind trial which randomized 65 patients (2:1) to evinacumab (15 mg/kg of body weight) every 4 weeks (43 patients) or a matching placebo (22 patients). Patients must have been at least 12 years old, on maximally-tolerated lipid-lowering therapy and must have had an LDL-C level of ≥70 mg/dL. The primary endpoint was % change from the baseline in LDL-C level at week 24.

At week 24, the % LDL-C change from baseline was -47.1% in the evinacumab group and +1.9% in the placebo group (treatment difference of -49.0%; 95% confidence interval [CI] -65.0% to -33.1%; P <.001), demonstrating a significant LDL-C–lowering effect of evinacumab. A reduction in LDL-C in the evinacumab group was already apparent at 2 weeks after treatment began (Figure 30-2, which also shows the absolute LDL-C reduction).

The FDA approved evinacumab for use in patients with HoFH on the basis of these results.

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Patients with Refractory Familial Hypercholesterolemia

The LDL-C-lowering efficacy of evinacumab in patients with refractory hypercholesterolemia (with or without HeFH) was assessed in a double-blind, placebo-controlled trial which randomized 272 patients to: 1) subcutaneous (SC) evinacumab 450 mg weekly (40 patients); 2) SC evinacumab 300 mg weekly (43 patients); 3) SC evinacumab 300 mg every 2 weeks (39 patients); 4) SC placebo (41 patients); 5) intravenous (IV) evinacumab 15 mg/kg every 4 weeks (39 patients); 6) IV evinacumab 5 mg/kg every 4 weeks (36 patients); or 7) IV placebo (34 patients). Patients must have been 18 to 80 years of age, and must have had primary hypercholesterolemia, defined as either HeFH or non–HeFH with clinical ASCVD, that was refractory to maximally tolerated LDL-C-lowering therapy (statin and a PCSK9 inhibitor, with or without ezetimibe). The primary endpoint was % change from the baseline in LDL-level at week 16.

For SC evinacumab, the % change in LDL-C at week 16 was -47.2% in the evinacumab 450 mg weekly group, -44.0% in the evinacumab 300 mg weekly group, -29.7% in the evinacumab 300 mg every 2 weeks and +8.8% in the placebo group (treatment difference against the placebo: -56.0% for evinacumab 450 mg weekly [95% CI -73.7% to -38.3%], -52.9% for 300 mg weekly [95% CI -70.7% to -35.1%] and -27.9% for 300 mg every 2 weeks [95% CI -56.5% to -20.6%]; P <.001 for all comparisons). For IV evinacumab, the % change in LDL-C was -49.8% in the evinacumab 15 mg/kg every 4 weeks group, -23.5% in the evinacumab 5 mg/kg every 4 weeks group and +0.6% in the placebo group (treatment difference against the placebo: -50.5% for evinacumab 15 mg/kg every 4 weeks [95% CI -68.4% to -32.6%], -24.2% for evinacumab 5 mg/kg every 4 weeks [95% CI -42.6% to -5.7%]; P <.001 for evinacumab 15 mg/kg every 4 weeks and not assessed for evinacumab 5 mg/kg every 4 weeks).

These data suggest that evinacumab is efficacious for LDL-C lowering in patients with refractory FH, including HeFH and non–HeFH and that it can be efficacious when administered subcutaneously, which may be more attractive to some patients as it does not require a healthcare professional for administration. However, the FDA has not yet approved evinacumab for SC administration or for hypercholesterolemia other than HoFH (see the Appropriate Uses section above).

ASCVD and Mortality Outcomes

No data are yet available on ASCVD risk reduction or mortality outcomes for evinacumab.

Effects on Other Lipids and Lipoproteins

Patients with Homozygous Familial Hypercholesterolemia

In addition to the % change in LDL-C (the primary endpoint), the ELIPSE HoFH trial assessed the % change in several other lipids and lipoproteins. At week 24, treatment with evinacumab 15 mg/kg every 4 weeks resulted in statistically significant % reductions from baseline in apoB (evinacumab -41.3%, placebo -4.5%; treatment difference -36.9% [95% CI -48.6% to -25.2%]; P <.001), non-HDL-C (evinacumab -49.7%, placebo +2.0%; treatment difference -51.7% [95% CI -64.8% to -38.5%]; P <.001) and total cholesterol (evinacumab -47.4%, placebo +1.0%; treatment difference -48.4% [95% CI -58.7% to -38.1%]; P <.001). Evinacumab treatment also resulted in a numerically greater % decrease in triglyceride, lipoprotein (a) (Lp(a)) and apoC3 levels.

Patients with Refractory Familial Hypercholesterolemia

In the trial of evinacumab efficacy among patients with refractory FH, numerically greater reductions in apoB, non-HDL-C, total cholesterol, triglycerides and Lp(a) occurred with all doses and both regimens (SC and IV) of evinacumab, compared to the placebo.

Dosing

Evinacumab is administered as an intravenous infusion, given by a healthcare professional. The recommended dose is 15 mg/kg over 60 minutes once monthly (every 4 weeks).

LDL-C levels should be assessed as clinically appropriate; an LDL-C-lowering effect may be apparent as early as 2 weeks after the initial infusion.

A missed dose of evinacumab should be administered as soon as possible and the once-monthly dosing schedule resumed from that dose.

Contraindications

The only contraindication for evinacumab is a history of serious hypersensitivity reactions to evinacumab or to any of the drug excipients.

Safety

Warnings and Precautions

Serious hypersensitivity reactions may occur in patients taking evinacumab. In clinical trials, 1 patient in the evinacumab group (1%) experienced anaphylaxis, compared to no patients in the placebo group. Evinacumab should be discontinued if signs or symptoms of serious hypersensitivity occur.

Data from animal reproductive studies suggest that evinacumab may cause fetal toxicity if administered to pregnant patients.

Adverse Reactions

According to pooled data from ELIPSE-HoFH and another randomized, double-blind, placebo-controlled trial of evinacumab, the most common adverse events which occurred at a rate of >3% and were numerically more common with evinacumab (n=81) than with placebo (n=54) included: nasopharyngitis (16% vs 13% in the evinacumab and the placebo group, respectively), influenza-like illness (7% vs 6%), dizziness (6% vs 0%), rhinorrhea (5% vs 0%), nausea (5% vs 2%), pain in extremity (4% vs 0%) and asthenia (4% vs 0%). Among patients who received evinacumab, 2 patients (2%) discontinued the treatment because of adverse reactions, compared to 1 patient (1%) who received the placebo.

Specific Populations

As mentioned above, evinacumab may cause embryofetal toxicity based on animal studies. However, human data are lacking. Patients receiving evinacumab who may become pregnant should be informed of the potential risk to the fetus and advised to use effective contraception while receiving evinacumab and for at least 5 months following the last dose. Before initiating evinacumab, consider obtaining a pregnancy test. There are no data on the presence of evinacumab in breast milk. The developmental and health benefits of breastfeeding should be weighed against the clinical benefit of evinacumab for the breastfeeding mother and the potential risks to the infant of evinacumab exposure through breast milk.

The safety and efficacy of evinacumab have not been established in children younger than 12 years of age. Clinical trials of evinacumab did not include enough elderly patients (65 years of age and older) to assess whether they respond differently.

There are no data available in patients with hepatic impairment or patients with severe renal impairment. The pharmacokinetics of evinacumab in patients with mild and moderate renal impairment is similar to that in patients with normal renal function.

Drug-Drug Interactions

No drug-drug interaction studies have been conducted with evinacumab. Data from clinical trials indicate that concentrations of atorvastatin, rosuvastatin and simvastatin are not significantly altered after administration of evinacumab and that concentrations of evinacumab were similar among patients with HoFH regardless of whether they were on background lipid-lowering therapy or not.