Regeneron Pharmaceuticals, Inc. today 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."

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 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.

About Evinacumab

Evinacumab is an investigational, fully-human, monoclonal antibody that specifically binds to angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 acts as an inhibitor of lipoprotein lipase and endothelial lipase, and appears to play a central role in lipoprotein metabolism. It is currently being studied in patients with HoFH (Phase 3), refractory hypercholesterolemia (Phase 2) and severe hypertriglyceridemia (Phase 2).

About the ELIPSE HoFH Trial 

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). The primary endpoint is reduction of LDL cholesterol with evinacumab 15 mg/kg compared to placebo after 24 weeks. Secondary endpoints evaluate safety, tolerability and pharmacokinetics (PK), as well as the efficacy of evinacumab on LDL cholesterol goal attainment and other lipid parameters (including ApoB and non-HDL cholesterol) and whether patients met criteria for needing LDL apheresis. The trial was not powered to evaluate the effect of evinacumab on cardiovascular events.

The average age of patients entering the trial was 42 years (range: 12 to 75). 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 trial has three treatment periods: 1) up to an eight-week run-in period; 2) a 24-week double-blind treatment period (DBTP); 3) and an ongoing, 24-week, open-label treatment period (OLTP). During the OLTP portion of the trial, which is ongoing, all patients receive evinacumab, regardless of treatment assignment in the DBTP.

About Regeneron 

Regeneron is a leading biotechnology company that invents life-transforming medicines for people with serious diseases. Founded and led for 30 years by physician-scientists, our unique ability to repeatedly and consistently translate science into medicine has led to seven FDA-approved treatments and numerous product candidates in development, all of which were homegrown in our laboratories. Our medicines and pipeline are designed to help patients with eye disease, allergic and inflammatory diseases, cancer, cardiovascular and metabolic diseases, infectious diseases, pain and rare diseases.

Regeneron is accelerating and improving the traditional drug development process through our proprietary VelociSuite® technologies, such as VelocImmune® which produces optimized fully-human antibodies, and ambitious research initiatives such as the Regeneron Genetics Center, which is conducting one of the largest genetics sequencing efforts in the world.

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