51成人动漫

Patients with refractory familial hypercholesterolemia that cannot be controlled with statins and PCSK9 inhibitors appeared to respond to evinacumab, a novel, fully human monoclonal antibody that inhibits angiopoietin-like 3 (ANGPTL3), a phase II study indicated.

Among patients given higher doses of evinacumab in the randomized, placebo-controlled trial -- either by subcutaneous or intravenous infusion -- LDL was reduced by about 50%, reported Robert Rosenson, MD, of the Icahn School of Medicine at Mount Sinai in New York City.

In patients treated intravenously every 4 weeks with evinacumab 15 mg/kg, there was a 49.9% decrease in LDL by week 16 of the study, compared with a 0.6% increase among patients assigned to placebo (P<0.001), according to findings presented at the 2020 virtual scientific sessions of the American Heart Association (AHA) and published simultaneously in the .

The researchers also tested three different dosing and scheduling regimes for the subcutaneous injections of evinacumab. Patients on the highest evinacumab dose (450 mg weekly) achieved a 47.2% decrease in LDL compared with an 8.8% increase among placebo patients in this arm of the study (P<0.001).

"Results of this trial and previous studies suggest," Rosenson said, "that 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."

All patients in the study were considered refractory to treatment, despite almost all of them being on PCSK9 inhibitors and about half on high-intensity statins at the maximum tolerated dose. Another 30% of the patients had ezetimibe (Zetia) on board as well.

Evinacumab targets ANGPTL3, which regulates lipid metabolism by inhibiting lipoprotein lipase and endothelial lipase. People who have loss-of-function variants of ANGPTL3 often have low levels of LDL and triglycerides. Proof of concept phase II studies showed that the ANGPTL3 monoclonal antibody was effective in patients with lower cholesterol levels, which led to the current study.

"High levels of ANGPTL3 lead to high levels of triglycerides and to high levels of cholesterol," Salim Virani, MD, PhD, of Baylor College of Medicine in Houston, told 51成人动漫.

"This particular agent has been shown to lower high levels of triglycerides in the 50% to 60% level, and also to lower LDL cholesterol as well," said Virani, who was not involved in the study. "Because evinacumab lowers both triglycerides and LDL cholesterol, it makes these results presented at the AHA meeting pretty exciting."

Virani said evinacumab is interesting because of its ability to lower out-of-range lipids using a different mechanism of action than statins and PCSK9 inhibitors.

"This is an area of need, and that was the population that was targeted by the investigators in this study," he noted. "We need long-term studies to see if evinacumab's ability to lower LDL cholesterol translates into improvement in hard cardiovascular outcomes. We are cautiously optimistic about this drug, but we need large phase III studies."

As far as adverse events were concerned, Virani said there was "nothing that stands out as a problem, but we should note that the ANGPTL3 medications also tends to lower high density lipoprotein [HDL] cholesterol -- the good cholesterol. We have to see if the lower HDL levels have any impact on cardiovascular outcomes."

In all, 266 evaluable patients were included in the current study. Patients were in their 50s, about 62% were women, and 91% were white. Patients had an average body mass index of 28.6, 54% had been diagnosed with coronary artery disease, and the average calculated LDL was 150 mg/dL. Familial hypercholesterolemia was identified in 81% of the 106 participants in the intravenous group and in 72% of the 160 participants in the subcutaneous group.

In the subcutaneous arm, 40 patients received a dose of 450 mg weekly, 43 received 300 mg weekly, and 39 received a dose of 300 mg every 2 weeks, which was compared with a placebo arm of 41 patients. In the intravenous arm, evinacumab was administered in 39 patients at a dose of 15 mg/kg every 4 weeks and in 36 at a dose of 5 mg/kg, which was compared with a separate placebo arm of 34 patients.

The lower-dose IV arm showed a 23.5% reduction in LDL at week 16. In the lower-dose subcutaneous arms, there was a 44% reduction in LDL among patients treated with evinacumab 300 mg weekly and a 29.7% reduction among patients who received evinacumab 300 mg every 2 weeks, significant improvements over placebo (P<0.001 for both), said Rosenson.

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