FDA Approves First-in-Class Therapy for Ultra-Rare Form of High Cholesterol


Evinacumab-dgnb (Evkeeza; Regeneron Pharmaceuticals, Inc.) is the first FDA-approved treatment that binds to and blocks the function of angiopoietin-like 3 (ANGPTL3), a protein that plays a key role in lipid metabolism.

Officials with the FDA have approved evinacumab-dgnb (Evkeeza; Regeneron Pharmaceuticals, Inc.) as an adjunct to other low-density lipoprotein cholesterol (LDL-C) lowering therapies to treat patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH). According to Regeneron, evinacumab-dgnb is the first FDA-approved treatment that binds to and blocks the function of angiopoietin-like 3 (ANGPTL3), a protein that plays a key role in lipid metabolism.

HoFH, also known as homozygous FH, is an ultra-rare inherited condition that affects approximately 1300 patients in the United States HoFH occurs when 2 copies of the familial hypercholesterolemia (FH)-causing genes are inherited, 1 from each parent, resulting in dangerously high levels (>400 mg/dL) of LDL-C. Patients with HoFH are at risk for premature atherosclerotic disease and cardiac events as early as their teenage years.

According to Daniel J. Rader, MD, professor and chair of the Department of Genetics in the Perelman School of Medicine of the University of Pennsylvania, and a leading HoFH expert who was involved with the evinacumab-dgnb clinical trials, the drug has the potential to transform treatment for people with HoFH.

"Existing therapies for HoFH are insufficient for the majority of patients. Evkeeza, through its unique mechanism of action, was shown to reduce LDL-C levels in patients with all forms of HoFH, even those with nearly no LDL receptor activity, and represents a highly meaningful improvement in our ability to control LDL-C levels in patients with HoFH."

The FDA approval is based on results from the phase 3 ELIPSE HoFH trial. In the trial, 65 patients were randomized to receive either evinacumab-dgnb 15 mg/kg intravenously every 4 weeks (n=43) plus other lipid-lowering therapies, compared to lipid-lowering therapies alone (placebo, n=22). The mean baseline LDL-C level of patients in both groups was 255 mg/dL.

The trial met its primary endpoint, with patients treated with evinacumab-dgnb reducing their LDL-C from baseline by 49% on average compared to placebo at week 24 (47% reduction evinacumab-dgnb, 2% increase placebo, p<0.0001). At the same time point, compared to baseline, patients treated with evinacumab-dgnb also experienced the following:

  • 132 mg/dL average reduction in LDL-C compared to placebo (135 mg/dL reduction evinacumab-dgnb, 3 mg/dL reduction placebo, p<0.0001).
  • Significant reductions were also observed in other key secondary endpoints including levels of apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C) and total cholesterol, compared to placebo (p<0.0001 for all).
  • Similar levels of LDL-C lowering were also observed in the most difficult-to-treat patients who often don't respond to certain other therapies because of limited LDL receptor function, described as "null/null" (<15% LDL receptor function by in vitro assays) or "negative/negative" patients.

Reductions in LDL-C seen with evinacumab-dgnb were observed as early as week 2 and maintained throughout the double-blind treatment period (week 24) and open label trial period (through week 48).

The most common adverse reactions (more than 3% of patients) reported from the combined safety analysis of placebo-controlled trials after 24 weeks that occurred more frequently in patients treated with evinacumab-dgnb (n=81) than placebo (n=54) were nasopharyngitis (16% evinacumab-dgnb, 13% placebo), influenza-like illness (7% evinacumab-dgnb, 6% placebo), dizziness (6% evinacumab-dgnb, 0% placebo), rhinorrhea (5% evinacumab-dgnb, 0% placebo), nausea (5% evinacumab-dgnb, 2% placebo), pain in extremity (4% evinacumab-dgnb, 0% placebo) and asthenia (4% evinacumab-dgnb, 0% placebo). In clinical trials, adverse reactions led to discontinuation of treatment in 2% of patients treated with evinacumab-dgnb, including 1 case of anaphylaxis that resolved with treatment, and 2% of patients who received placebo.

Evinacumab-dgnb is administered based on weight (15 mg/kg) once a month via intravenous infusion.

The average Wholesale Acquisition Cost per patient in the United States will vary based on weight, and is expected to be approximately $450,000 per year on average. According to Regeneron, the company's myRARE patient support program offers financial assistance to eligible patients who need help with the out-of-pocket cost of evinacumab-dgnb.


FDA approves first-in-class Evkeeva (evinacumab-dgnj) for patients with ultra-rare inherited form of high cholesterol [news release]. Tarrytown, NY; February 11, 2021: Regeneron. Accessed February 11, 2021. https://investor.regeneron.com/node/24876/pdf

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