ANGPTL3 antibody halves LDL-c levels in HoFH patients in phase 3 trial
Positive phase 3 results of the ELIPSE HoFH trial have been announced for evinacumab, an investigational angiopoietin-like 3 (ANGPTL3) antibody, in patients with homozygous familial hypercholesterolemia (HoFH). ANGPTL3 acts as an inhibitor of lipoprotein lipase (LPL) and endothelial lipase, and appears to play a central role in lipoprotein metabolism.
On average, patients entered the trial with LDL-c levels of 255 mg/dL, despite treatment with other lipid-lowering therapies, including maximally-tolerated statins, PCSK9 inhibitors, ezetimibe, LDL apheresis and lomitapide. The trial met its primary endpoint, showing that adding evinacumab to other lipid-lowering therapies decreased LDL-c by 49% on average, compared to lipid-lowering therapies alone.
ELIPSE HoFH is an ongoing phase 3 randomized, double-blind, placebo-controlled, parallel-group trial evaluating the efficacy and safety of evinacumab 15 mg/kg administered intravenously every four weeks in 65 patients aged 12 years or older with HoFH (43 evinacumab, 22 placebo). In the evinacumab treatment group, 98% of patients were on statins, 81% were on PCSK9 inhibitors, 75% were on ezetimibe, 33% were on LDL apheresis and 26% were on lomitapide. In addition, 35% of evinacumab patients had the most severe, "null/null" form of HoFH.
The phase 3 trial was designed to assess the effect of evinacumab on LDL-c and other lipid-related endpoints. Results from the evinacumab group at week 24 included:
- 49% reduction in LDL-c from baseline, compared to placebo (47% reduction for evinacumab vs. 2% increase for placebo, P<0.0001), the primary endpoint. LDL-c reductions were observed from the first assessment at week 2, and were maintained throughout the 24-week double-blind treatment period.
- 132 mg/dL absolute change in LDL-c from baseline, compared to placebo (135 mg/dL reduction vs. 3 mg/dL reduction, P<0.0001).
- 47% achieved LDL-c levels less than 100 mg/dL, compared to 23% for placebo (nominal P=0.0203).
- Similar levels of LDL c-lowering were also observed in “null/null" patients who often do not respond to other therapies.
- Evinacumab also reduced ApoB, non-HDL-c and total cholesterol compared to placebo.
In the trial, evinacumab was generally well-tolerated. During the double-blind treatment period, 66% of evinacumab patients and 81% of placebo patients experienced an adverse event (AE). AEs that occurred in at least 5% of patients and more commonly with evinacumab were influenza-like illness (11% evinacumab, 0% placebo) and rhinorrhea (7% evinacumab, 0% placebo). During the double-blind treatment period there was no difference in the incidence of nausea, abdominal pain or diarrhea between treatment groups, and there were no deaths, major adverse cardiovascular events or hepatic disorders.
In 2017, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for evinacumab for the treatment of hypercholesterolemia in patients with HoFH. Regeneron scientists discovered the angiopoietin gene family more than two decades ago. Human genetics research published in the New England Journal of Medicine in 2017 by scientists from the Regeneron Genetics Center found that patients with an ANGPTL3 loss-of function mutation have significantly lower levels of key blood lipids, including LDL-c, and this is associated with a significantly lower risk of coronary artery disease.
In an ongoing, 24-week, open-label treatment period of the ELIPSE HoFH trial, all patients receive evinacumab, regardless of treatment assignment in the double-blind treatment period. An ongoing phase 2 trial is also evaluating the efficacy and safety of the ANGPTL3 antibody in patients with severe hypertriglyceridemia at risk for acute pancreatitis.