In two different phase 3 studies, the PCSK9 inhibitors alirocumab and novel evinacumab substantially reduced LDL-C levels in adults with homozygous familial hypercholesterolemia (HoFH). The results of the two studies were presented March 30 in a Late-Breaking Clinical Trial session during ACC.20/WCC.

The ODYSSEY HoFH study with alirocumab is the first placebo-controlled trial to assess the efficacy and safety of the drug in HoFH patients. Alirocumab is approved by the U.S. Food and Drug Administration to treat high LDL-C in adults alone or combined with other lipid-lowering therapies. In the study, 45 patients were randomly assigned to receive alirocumab 150 mg via subcutaneous injection every two weeks for 12 weeks and 24 to placebo injections. All patients maintained their usual lipid-lowering treatment regimen, but did not take any other PCSK9 inhibitors.

At 12 weeks, LDL-C levels were 26.9% lower in the alirocumab vs. 8.6% higher in the placebo group, resulting in an average relative reduction of 35.6% among alirocumab recipients (p<0.0001), meeting the trial’s primary endpoint. The average absolute reduction in LDL-C was 62.8 mg/dL in patients receiving alirocumab.

Alirocumab was well-tolerated and no treatment-related serious adverse events occurred.

“This trial is the largest randomized controlled interventional trial in adults with HoFH to date and offers important insights into the disease,” says Dirk Blom, MD, PhD, the study’s lead author. “Alirocumab is a potential new therapy that should be considered in appropriate patients with HoFH.” He notes, “Unfortunately, there is also a small number of patients with specific mutations who do not respond, or only respond very poorly, to alirocumab.”

A separate study examined the investigational evinacumab, also a monoclonal antibody, which binds to angiopoietin-like protein 3 (ANGPTL3). By targeting ANGPTL3, evinacumab is designed to reduce LDL-C through a different mechanism than any existing drug. 

“For the first time, we were able to get these patients with HoFH to remarkably normal LDL-C levels,” says Frederick J. Raal, PhD, lead author of the phase 3 trial testing evinacumab. “It’s the most potent cholesterol-lowering drug we’ve seen for this very difficult-to-treat group of patients.”

Researchers enrolled 65 patients with HoFH, of whom about three-quarters were on triple therapy (high intensity statin, a PCSK9 inhibitor and ezetimibe) and one-third were also on regular apheresis. On top of their usual lipid-lowering treatment regimen, 43 were randomized to evinacumab 15 mg/kg via intravenous infusion every four weeks for 24 weeks and 22 to placebo infusions.

Results showed a striking reduction in LDL-C starting at week two with evinacumab. At week 24, average LDL-C levels had been reduced by 47.1% while LDL-C levels among those receiving placebo rose by 1.9%, resulting in an average relative reduction of 49% among patients receiving evinacumab (p<0.0001), meeting the trial’s primary endpoint. 

In terms of absolute LDL-C levels, a key secondary endpoint, patients receiving evinacumab had an average drop of 132 mg/dL (p<0.0001). Nearly half of individuals receiving evinacumab achieved an LDL-C below 100 mg/dL.

Reductions in LDL-C with evinacumab were similar in HoFH patients with absent LDL receptor function (null/null) and in those with some residual LDL receptor function (non-null). This is of major clinical significance, as null/null HoFH patients have the highest cardiovascular risk and are least responsive to currently available lipid-lowering drugs, Raal explains.

Adverse events occurred in 65.9% of patients receiving evinacumab and 81% of those receiving placebo. The most common adverse events were a cold, headache, fever, diarrhea and toothache. No serious treatment-related adverse events were observed.

The relatively short duration of treatment and the small number of patients limit the trial’s ability to draw conclusions regarding the long-term safety of evinacumab. The researchers plan to continue the study with an open-label extension to determine longer-term safety of evinacumab.

“The results are remarkable,” Raal says. “This is a promising add-on therapy for individuals with homozygous FH that addresses the unmet need to further lower LDL-C in these patients.”

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Nonstatins, Acute Heart Failure

Keywords: ACC Annual Scientific Session, acc20, Cholesterol, LDL, Dyslipidemias, Primary Prevention, Metabolic Syndrome, Heart Failure

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