Administration of evinacumab, an investigational angiopoietin-like 3 (ANGPTL3) antibody, either by injection or infusion, reduced LDL cholesterol levels by more than 50% in a phase II trial that enrolled persons with refractory hypercholesterolemia (with or without heterozygous familial hypercholesterolemia [HeHF]).
Given on top of maximum lipid-lowering therapy—including use of PCSK9 inhibitors — 16 weeks of treatment achieved reductions from baseline LDL of −56.0% at 450 mg weekly injection, −52.9%, at 300 mg weekly injection, and −38.5% at 300 mg every 2 weeks (P< 0.001) for all comparisons, Robert S. Rosenson, MD, of the Icahn School of Medicine at Mount Sinai in New York, and colleagues. They reported the findings in The New England Journal of Medicine and at the American Heart Association’s virtual Scientific Sessions 2020.
“The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were −50.5 percentage points (P<0.001) and −24.2 percentage points, respectively,” they wrote.
In addition to the LDL lowering, treatment with evinacumab reduced HDL. “Reduction in the HDL cholesterol level has been observed in dyslipidemic or normolipidemic mouse models after targeted inactivation of ANGPTL3; this reduction is due to derepression of endothelial lipase, which is a consequence of ANGPTL3 blockade… The importance of the reduction in the HDL cholesterol level observed with evinacumab remains to be fully elucidated, but in patients with a naturally occurring genetic ANGPTL3 deficiency, low HDL cholesterol levels are not associated with an increased risk of cardiovascular disease,” they wrote.
Positive topline results of an evinacumab trial in homozygous familial hypercholesterolemia (HoFH trial) were announced last August by the drug maker Regeneron and the FDA granted priority review for evinacumab for treatment of HoHF.
The trial enrolled 272 patients, but six patients did not receive a trial agent, so the intention-to-treat analysis included 160 patients assigned to subcutaneous treatment and 106 to infusion treatment. In the injection group, 72% had HeFH and in the infusion group, 81% had HeFH.
“The baseline mean (±SD) LDL cholesterol level was similar among patients assigned to receive evinacumab at a dose of 450 mg weekly (146.3±84.6 mg per deciliter [3.78±2.19 mmol per liter]), evinacumab at a dose of 300 mg weekly (159.1±73.0 mg per deciliter [4.11±1.89 mmol per liter]), and placebo (157.8±92.4 mg per deciliter [4.08±2.39 mmol per liter]) but was lower among patients assigned to receive evinacumab at a dose of 300 mg every 2 weeks (136.2±70.2 mg per deciliter [3.52±1.82 mmol per liter]). All the patients were receiving a PCSK9 inhibitor, 44% were receiving a high-intensity statin (with all these patients receiving a maximum tolerated dose of the statin), and 30% were receiving ezetimibe,” they wrote.
Participants assigned to infusion treatment received “evinacumab at a dose of 15 mg per kilogram (143.1±54.4 mg per deciliter [3.70±1.41 mmol per liter]), evinacumab at a dose of 5 mg per kilogram (146.0±61.0 mg per deciliter [3.78±1.58 mmol per liter]), and placebo (144.5±46.6 mg per deciliter [3.74±1.21 mmol per liter]).” Here, too, patients were receiving optimal LDL-lowering therapy including high dose statins, PCSK9 inhibitors, and ezetimibe.
Rosenson and colleagues noted that the patients enrolled in the trial represent an especially challenging group, which despite rigorous treatment regimens that employ a wide-range of agents, have a “residual unmet need, which is particularly relevant in the context of the 2019 ESC–EAS lipid-management guidelines, which specify a target LDL cholesterol level of less than 55 mg per deciliter for patients with very high risk for atherosclerotic cardiovascular disease; the 2016 ESC–EAS guidelines and the 2018 ACC–AHA guidelines recommended a target LDL cholesterol level of less than 70 mg per deciliter in patients with very high risk for atherosclerotic cardiovascular disease. In addition, some patients with heterozygous familial hypercholesterolemia may have adverse events associated with standard-of-care lipid-lowering therapies, which limit the optimization of treatment regimens.”
Moreover, although studies have found that treatment with a PCSK9 inhibitor “reduces the risk of major cardiovascular events by more than 50%, a real-world study involving 204 patients with heterozygous familial hypercholesterolemia and very high risk for cardiovascular disease showed that only 39% had an LDL cholesterol level of less than 55 mg per deciliter despite treatment with PCSK9 inhibitors.”
The researchers noted a number of limitations, including a small sample size and a lack of racial diversity, which taken together limit “robust conclusions pertaining to long-term safety.”
Nonetheless, they concluded that the findings suggest evinacumab is “effective in lowering LDL cholesterol levels in patients with refractory hypercholesterolemia, including homozygous familial hypercholesterolemia, refractory heterozygous familial hypercholesterolemia, and hypercholesterolemia of an undetermined cause.”
Be aware that this activity describes efficacy of a drug that is not yet FDA approved for clinical use.
In a phase II trial both subcutaneous and infusion treatment with eveinacumab at maximum dose given on top of optimal lipid-lowering therapy achieved significant reductions in LDL cholesterol among persons with refractory hyperholesterolemia.
Peggy Peck, Editor-in-Chief, BreakingMED™
The trial was supported by Regeneron Pharmaceuticals.
Rosenson reported grants and personal fees from Regeneron, grants and personal fees from Amgen, grants and personal fees from Medicines Company, grants from Novartis, personal fees from CVS Caremark, personal fees from Kowa, personal fees from Corvidia, personal fees from 89Bio, other from UpToDate, other from MediMergent, LLC, outside the submitted work.
Cat ID: 232
Topic ID: 74,232,232,308,4,5,914,192,925,231