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Regeneron Reports Positive Results of Two Therapies in Patients with Severe Inherited Form of High Cholesterol

March 31, 2020

In separate presentations, Regeneron Pharmaceuticals reported detailed positive phase 3 results of two of its therapies, evinacumab and Praluent (alirocumab), in patients with homozygous familial hypercholesterolemia.

Investigators made the presentation at the American College of Cardiology’s Annual Scientific Session together with World Congress of Cardiology.

Homozygous familial hypercholesterolemia (HoFH) is an inherited disease in which patients have severely elevated levels of bad cholesterol (otherwise known as low-density lipoprotein cholesterol, or LDL-C) and often experience early atherosclerotic disease, sometimes suffering cardiac events in their teenage years. Most patients with HoFH are less or non-responsive to standard lipid-lowering therapies, including statins and PCSK9 inhibitors, which act mainly by inducing LDL receptor function, leaving these patients with high unmet need.

Evinacumab is an experimental fully-human monoclonal antibody that binds to and blocks the function of angiopoietin-like 3 (ANGPTL3), in patients with HoFH. It acts by a different mechanism than other lipid-lowering therapies, raising the possibility that it might offer patients with HoFH profound LDL-C reductions. Supporting this possibility, genetic research has shown that reduction of ANGPTL3 is associated with decreased LDL-C levels, as well as significantly lower risk of coronary artery disease.

In the randomized, placebo-controlled phase 3 trial, 65 patients with HoFH aged 12 years or older who added evinacumab to other lipid-lowering therapies reduced their LDL-C by 49 percent from baseline at 24 weeks compared to the placebo group, who received other lipid-lowering therapies alone, meeting the primary endpoint of the trial. Nearly all (95 percent) patients in the evinacumab arm entered the trial on statins and 79 percent were on PCSK9 inhibitors. Nearly half of evinacumab-treated patients reduced LDL-C to under 100 mg/dL, despite entering the trial with average LDL-C levels of 260 mg/dL on other lipid-lowering therapies. 

Significant reductions were also observed in other key secondary endpoints including levels of apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol, and triglycerides, compared to placebo. 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. Evinacumab was generally well-tolerated.

“As a doctor, it can be heart-wrenching to see HoFH patients struggle to lower their potentially life-threatening LDL-C levels, despite taking every medical treatment available to them,” said Professor Derick Raal, principal investigator and professor and head of the division of Endocrinology & Metabolism at the University of the Witwatersrand, South Africa. “In this trial, for the first time, evinacumab-treated HoFH patients lowered their LDL-C to previously unattainable levels, with nearly half achieving an LDL-C range that is considered ‘normal’ for healthy adults.”

Evinacumab was granted Breakthrough Therapy designaton by the U.S. Food and Drug Administration in 2017. Regeneron previously announced topline positive results of this trial in August 2019. The detailed results will be used as the basis of regulatory submissions around the world, with and FDA submission expected to be completed by mid-2020.

“Despite medical advances, cardiovascular disease tragically remains the number one cause of death for men and women worldwide,” said George Yancopoulos, co-founder, president and chief scientific officer of Regeneron. “Our investments in genetic research and biology enable us to identify completely new ways of targeting diseases. Evinacumab, a first-of-its-kind antibody that works entirely differently to other HoFH medicines, exemplifies the potential of genetic-based research to revolutionize patient treatment.”

Regeneron also presented phase 3 results demonstrating the effect of Praluent (alirocumab) on patients with HoFH. Praluent is approved in more than 60 countries around the world to reduce the risk of heart disease, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.

The Praluent trial in patients with HoFH met its primary endpoint, with Praluent-treated patients reducing their LDL-C by more than a third at week 12, compared to placebo. In addition, more than a quarter of patients reduced their LDL-C by at least half, despite entering the trial with average LDL-C levels of 295 mg/dL while being on other lipid-lowering therapies and/or apheresis. No new safety signals were identified in the trial.

Praluent inhibits the binding of PCSK9 to the LDL receptor and thereby increases the number of available LDL receptors on the surface of liver cells to clear LDL, which lowers LDL-C levels in the blood. Praluent was invented by Regeneron and developed with Sanofi under a global collaboration agreement.  

Author: Rare Daily Staff

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