Regeneron Pharmaceuticals, Inc. announced positive pivotal Phase 3 results for evinacumab, an investigational angiopoietin-like 3 (ANGPTL3) antibody, in patients with homozygous familial hypercholesterolemia (HoFH). Patients with HoFH have severely elevated levels of bad cholesterol (otherwise known as low-density lipoprotein cholesterol, or LDL cholesterol), and often experience early atherosclerotic disease, sometimes suffering cardiac events as early as their teenage years.
On average, patients entered the trial with LDL cholesterol levels of 255 mg/dL, despite treatment with other lipid-lowering therapies, including maximally-tolerated statins, PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, ezetimibe, LDL apheresis and lomitapide. The trial met its primary endpoint, showing that adding evinacumab to other lipid-lowering therapies decreased LDL cholesterol by 49% on average, compared to lipid-lowering therapies alone.
“Currently HoFH patients face limited choices in reducing their LDL cholesterol, including therapies that are time-consuming like LDL apheresis, or that may have side effect concerns. Despite recent therapeutic advances, there is still a significant unmet need to lower the LDL cholesterol of many patients with HoFH. On average, evinacumab reduced patients’ LDL cholesterol in half and was generally well-tolerated in the trial,”
said George D. Yancopoulos, M.D., Ph.D., President and Chief Scientific Officer of Regeneron.
“These results raise the potential that evinacumab may have value for other patients with severe, refractory hypercholesterolemia, where we have a trial ongoing.”
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 whose ANGPTL3 gene did not function properly (called a “loss-of function mutation”) have significantly lower levels of key blood lipids, including LDL cholesterol, and this is associated with a significantly lower risk of coronary artery disease.
“People born with homozygous familial hypercholesterolemia – the rare and most severe form of FH – are in urgent need of additional therapies to lower life-threatening cholesterol levels. HoFH causes aggressive heart disease even in childhood, and today’s treatments often are not enough for these individuals,”
said Katherine Wilemon, Founder and Chief Executive Officer, FH Foundation.
“These evinacumab Phase 3 results bring hope to those who need it most. The FH Foundation is grateful to the researchers who advanced this science and the individuals who participated in this clinical trial.”
The Phase 3 trial was designed to assess the effect of evinacumab on LDL cholesterol and other lipid-related endpoints. Results from the evinacumab group at week 24 included:
- 49% reduction in LDL cholesterol from baseline, compared to placebo (47% reduction for evinacumab compared to a 2% increase for placebo, p<0.0001), the primary endpoint.
- 132 mg/dL absolute change in LDL cholesterol from baseline, compared to placebo (135 mg/dL reduction for evinacumab compared to a 3 mg/dL reduction for placebo, p<0.0001).
- 47% achieved LDL cholesterol levels less than 100 mg/dL, compared to 23% for placebo (nominal p=0.0203).
- Similar levels of LDL cholesterol-lowering were also observed in the most difficult-to-treat patients who often don’t respond to certain other therapies, described as “null/null” or “negative/negative” patients.
- Evinacumab also reduced apolipoprotein B (ApoB), non-HDL cholesterol and total cholesterol compared to placebo.
LDL cholesterol reductions were observed from the first assessment at week 2, and were maintained throughout the 24-week double-blind treatment period.
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.
HoFH is a serious, rare, genetic condition and affects approximately 1,300 people in the U.S. Detailed results from this trial will be presented at a future medical meeting, and data will be submitted to regulatory authorities, starting with the FDA in 2020.