Evolocumab scores big in paediatric HeFH

Monthly injections of the PCSK9* monoclonal antibody evolocumab effectively reduced plasma LDL-cholesterol (LDL-C), often referred to as the bad cholesterol, in teenagers with heterozygous familial hypercholesterolaemia (HeFH) already taking statins, with or without ezetimibe, the HAUSER-RCT has shown.

“Evolocumab treatment resulted in a 38.3 percent reduction in LDL-C from baseline to week 24 relative to placebo in this paediatric group,” reported lead investigator Dr Raul Santos from the University of São Paulo Medical School and Hospital Israelita Albert Einstein, San Paulo, Brazil at ESC 2020. “Evolocumab significantly improved all secondary and exploratory lipid parameters and its safety profile was similar to placebo.”

Touted as the first placebo-controlled randomized trial of a PCSK9 inhibitor in paediatric HeFH, HAUSER-RCT included 157 teenagers (mean age 13.7 years, 56 percent female) already on statins, with or without ezetimibe. LDL-C level at baseline was 130 mg/dL or higher and triglyceride level was at 400 mg/dL or less. They were randomized 2:1 to monthly subcutaneous injections of evolocumab 420 mg (n=104) or placebo (n=53). [N Engl J Med 2020;doi:10.1056/NEJMoa2019910]

By week 24 of treatment, average LDL-C levels declined 44.5 percent in the evolocumab group vs 6.2 percent in the placebo group (difference of 38.3 percentage points; p<0.001).

In absolute terms, mean LDL-C declined by 77.5 mg/dL with evolocumab vs 9.0 mg/dL with placebo a (difference of 68.6 mg/dL; p<0.001). Evolocumab also improved non-HDL-C and apolipoprotein B levels.

Adverse events were similar between evolocumab and placebo, so were laboratory abnormalities and injection site reactions.

“As patients were recruited from 23 countries, we believe the study provides an accurate picture of the safety and efficacy of evolocumab in paediatric FH patients worldwide,” said  senior investigator Dr Daniel Gaudet from the Université de Montréal and the ECOGENE-21 Clinical Research Center, Quebec, Canada.

“HeFH is the most common monogenic disorder affecting 1 in 250 individuals,” said Santos. “It is characterized by elevated levels of LDL-C from birth and consequently increases the risk of premature atherosclerotic cardiovascular disease.”

The condition is treatable but massively underdiagnosed. Only 10 percent of persons affected by HeFH are properly diagnosed. Majority of patients can reach their target LDL cholesterol levels with statins and ezetimibe. However, about 5–10 percent may need additional lipid lowering therapy to bring their LDL-C down.

FH toolbox effective

The challenge lies in improving FH diagnosis. “If one in the family has FH, the whole extended family should be tested,” Gaudet advised. “Our toolbox for treating FH is now sufficiently effective, so there’s no reason not to diagnose the disease. Evolocumab can be used to fill the gap in these patients.”

The positive results of HAUSER-RCT in younger patients with FH deserve to be highlighted, commented Dr Robert Eckel of the University of Colorado Hospital in Aurora, Colorado, US and past president of the American Heart Association.

Evolocumab was first approved in 2015 to reduce LDL-C in those who do not achieve their LDL goals on standard medication, including those with FH. An expanded indication was granted in 2017 for cardiovascular risk reduction.

The longest data yet for FH showed that LDL-C lowering with evolocumab is sustainable for up to 4 years. [J Am Coll Cardiol 2020;75:565-574] This is longer than the 2.2 years of follow-up in the FOURIER trial. [Stroke 2020;51:1546–1554]

An open-label extension study, HAUSER-OLE, is ongoing to evaluate 80 weeks of evolocumab when added to standard of care in paediatric HeFH or homozygous FH patients.