Evinacumab greatly reduces LDL in refractory hypercholesterolemia
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Evinacumab, a novel fully human monoclonal antibody against angiopoietin-like 3, reduced LDL by more than 50% compared with placebo in patients with refractory hypercholesterolemia, researchers reported.
The patient population included those with refractory hypercholesterolemia despite treatment with statins and other lipid-lowering therapies, Robert S. Rosenson, MD, FACC, FACP, FAHA, FNLA, FACCP, professor of medicine and director of cardiometabolic disorders at Icahn School of Medicine at Mount Sinai, said during a presentation at the virtual American Heart Association Scientific Sessions. He said all patients were taking a PCSK9 inhibitor plus maximally tolerated statin therapy with or without ezetimibe.
For the phase 2 study, 272 patients were randomly assigned to subcutaneous evinacumab (Regeneron) 450 mg per week, 300 mg per week or 300 mg every other week, or placebo; or IV evinacumab 15 mg per kg of body weight every 4 weeks, 5 mg per kg of body weight every 4 weeks, or placebo. All patients had refractory hypercholesterolemia; many had heterozygous familial hypercholesterolemia (FH) and those who did not had atherosclerotic CVD.
The drug targets angiopoietin-like 3 (ANGPTL3) and can reduce LDL independent of the LDL receptor, Rosenson said during the presentation. As Healio previously reported, evinacumab reduced LDL to nearly normal levels in patients with homozygous FH.
In the subcutaneous delivery and IV delivery populations, the evinacumab groups had greater LDL reduction compared with the placebo groups, Rosenson said.
In the subcutaneous delivery analysis (mean age, 54 years; 63% women; baseline LDL, 150 mg/dL), the difference in least-squares mean change in LDL from baseline to 16 weeks compared with placebo was –56 percentage points in the evinacumab 450 mg per week group, –52.9 percentage points in the evinacumab 300 mg per week group and –38.5 percentage points in the evinacumab 300 mg every other week group (P < .001 for all), Rosenson said during the presentation.
“There were changes in other atherogenic lipoproteins in subcutaneous administrations,” Rosenson said. “Dose-dependent reductions in apolipoprotein B, non-HDL cholesterol, total cholesterol and triglycerides were observed. There was a non-dose-dependent reduction in lipoprotein(a).”
In the IV delivery analysis (mean age, 55 years; 56% women; baseline LDL, 144.5 mg/dL), the difference in least-squares mean change in LDL from baseline to 16 weeks compared with placebo was –50.5 percentage points in the evinacumab 15 mg per kg of body weight group (P < .001) and –24.2 percentage points in the evinacumab 5 mg per kg of body weight group (P = .0109), he said.
“There were dose-dependent reductions in other atherogenic lipids, including ApoB, non-HDL cholesterol, total cholesterol and triglycerides, and reductions in Lp(a) that were equivalent at 16.5% with both doses.”
Rates of serious adverse events were low, he said.
The results were simultaneously published in The New England Journal of Medicine.
“This phase 2 study demonstrates that evinacumab reduces LDL and other atherogenic lipoproteins in patients with refractory hypercholesterolemia, and is generally well tolerated,” Rosenson said during the presentation. “The addition of evinacumab to standard-of-care lipid-lowering therapy in patients with refractory hypercholesterolemia may potentially facilitate more patients attaining guideline-defined LDL cholesterol goals, and in doing so, has the potential to reduce the risk of cardiovascular disease events and overall mortality.”
The data “give us hope for additional LDL lowering in patients with refractory hypercholesterolemia,” Cardiology Today Editorial Board Member Karol E. Watson, MD, PhD, FACC, professor of medicine/cardiology at David Geffen School of Medicine at UCLA and co-director of the UCLA Program in Preventive Cardiology, said in a discussant presentation. “We know that lowering LDL is the foundation of atherosclerotic cardiovascular disease risk reduction, and statins are the mainstay. We know that the addition of nonstatin therapies may be useful for high-risk patients if the LDL remains above threshold. Currently, we have ezetimibe and PCSK9 monoclonal antibodies that are recommended to add to statin therapy if further LDL reduction is needed, but perhaps we’ll have new agents like evinacumab in the future that can do that as well.”
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R. Todd Hurst, MD
This was an interesting study because it provides us with another tool for lowering LDL. In just about every instance where we can significantly lower LDL and ApoB, we see a significant decrease in future risk for CVD.
We now have three tools that have been proven to have CV outcome benefits: statins, ezetimibe and PCSK9 inhibitors. However, there is a small segment of the population that we still can’t get to target levels that we know are going to provide the most clinical benefit.
Evinacumab is a novel agent that does work in this population. Researchers previously demonstrated a 50% reduction in LDL in the homozygous familial hypercholesterolemia population. That is a very rare condition; approximately only 1,000 Americans have it. This study extrapolates those findings to a larger population of patients with heterozygous FH, but that is still a small population. It shows that people who cannot attain LDL goals on the three proven agents for whatever reason may benefit from this other option.
This is not a hard outcomes study, but the results are exciting because we now have another tool for a very limited but high-risk segment of the population.
The ultimate goal is outcomes data showing we can decrease CV events and death. There were agents such as niacin and the fibrates that showed they can improve the laboratory numbers but had no benefit for mortality. But because this medication may be the only option for people who are very high risk, it is likely to be used before we have such studies. We may not be able to get such data because the population is so small.
There was a high rate of adverse effects both in the evinacumab group and in the placebo group. This may be a function of how those were quantified. It did not seem like there were any signals of serious short-term adverse effects from the medication.
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Rosenson RS, et al. LBS.04: Fish oil, fancy drugs and frustrations in lipid management. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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