Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C). Current statistics indicate that HoFH affects an estimated 1,300 individuals in the U.S. Patients with HoFH often have LDL levels greater than 400 mg/dL and may also have atherosclerosis and cardiac events as early as adolescence. In the pivotal phase III ELIPSE HoFH trial, researchers discovered that adding evinacumab to standard lipid-lowering therapies, such as statins and proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, diminished LDL-C by nearly 50% at 24 weeks compared with placebo.

In a recent press release, the FDA announced the approval of  Evkeeza (evinacumab-dgnb) as an adjunct to other LDL-C–lowering therapies in patients aged 12 years and older with HoFH. Evkeeza is a fully-human monoclonal antibody that binds to and blocks the function of angiopoietin-like 3 (ANGPTL3). ANGPTL3 acts as an inhibitor of lipoprotein lipase and endothelial lipase and appears to play a central role in lipoprotein metabolism.

The FDA approval was based on results from the phase III ELIPSE HoFH trial published in The New England Journal of Medicine in August 2020. The primary outcome was the percent change from baseline in the LDL cholesterol level at week 24. Patients were randomly assigned in a 2:1 ratio (65 patients with homozygous familial hypercholesterolemia) received stable lipid-lowering therapy to receive an IV infusion of evinacumab (at a dose of 15 mg per kilogram of body weight) every 4 weeks or placebo. In this double-blind, placebo-controlled phase III study, Raal et al found that the average baseline LDL cholesterol level in the two groups was 255.1 mg per deciliter, despite the receipt of maximum doses of background lipid-lowering therapy.

At Week 24, patients in the evinacumab group had a relative decrease from baseline in the LDL cholesterol level of 47.1%, compared with an increase of 1.9% in the placebo group, for a between-group least-squares average difference of –49.0 percentage points (95% confidence interval [CI], –65.0 to –33.1; P <.001); the between-group least-squares average absolute difference in the LDL cholesterol level was –132.1 mg per deciliter (95% CI, –175.3 to –88.9; P <.001).

The LDL cholesterol level was lower in the evinacumab group than in the placebo group in patients with null–null variants (–43.4% vs. +16.2%) and in those with nonnull variants (–49.1% vs. –3.8%).

Adverse events were comparable in the two groups. The most common reported adverse reactions were nasopharyngitis (16% evinacumab, 13% placebo), influenza-like illness (7% evinacumab, 6% placebo), dizziness (6% evinacumab, 0% placebo), rhinorrhea (5% evinacumab, 0% placebo), nausea (5% evinacumab, 2% placebo), pain in extremity (4% evinacumab, 0% placebo), and asthenia (4% evinacumab, 0% placebo). In clinical trials, adverse reactions led to termination of treatment in 2% of patients treated with evinacumab, including one case of anaphylaxis that resolved with treatment, and 2% of patients who received placebo.

Raal et al concluded that in patients with HoFH receiving maximum doses of lipid-lowering therapy, the decrease from baseline in the LDL cholesterol level in the evinacumab group, as compared with the small increase in the placebo group, resulted in a between-group difference of 49.0 % percentage points at 24 weeks. Researchers also noted that in this phase III trial, evinacumab substantially lowered LDL cholesterol levels in patients with HoFH, regardless of the degree of their LDL-receptor function.

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