Pediatric Heterozygous FH: PCSK9 Inhibitor Makes a Dent in LDL

Teenagers with heterozygous familial hypercholesterolemia (HeFH) achieved large reductions in LDL cholesterol when monthly evolocumab (Repatha) injections were added to their usual lipid-lowering treatments in the randomized, placebo-controlled HAUSER-RCT trial.

Average LDL cholesterol levels in pediatric HeFH patients declined 44.5% from 184.3 mg/dL at baseline by week 24 of treatment with the PCSK9 inhibitor evolocumab, versus -6.2% with placebo (P<0.001), reported Daniel Gaudet, MD, PhD, of Université de Montréal and the ECOGENE-21 Clinical Research Center, Quebec, and colleagues.

In absolute terms, mean LDL declined by 77.5 mg/dL with evolocumab, versus a drop of 9.0 mg/dL with placebo (P<0.001).

Evolocumab also improved levels of non-HDL cholesterol and apolipoprotein B, the investigators added in their presentation at this year’s virtual European Society of Cardiology meeting. A full manuscript was simultaneously published online in the New England Journal of Medicine.

“With an estimated prevalence of 1 in 250 in the general population, HeFH is the most frequent monogenic disorder and a major heritable cause of atherosclerotic cardiovascular disease worldwide,” the authors noted.

Standard therapy consists of statins and ezetimibe, but LDL cholesterol may remain high in some HeFH patients due to limited drug response, side effects, or poor treatment adherence, according to Gaudet’s group. “The results of the present trial suggest that if an additional therapy is indicated, evolocumab might be considered.”

Despite being “fairly predictable,” the positive results of HAUSER-RCT do deserve to be highlighted as they confirm that evolocumab works well in younger people with familial hypercholesterolemia, commented Robert Eckel, MD, of University of Colorado Hospital in Aurora.

At this point, a long-term clinical trial would be very expensive, not to mention potentially unethical for a placebo group with very high LDL cholesterol, Eckel told MedPage Today.

Evolocumab was first FDA-approved in 2015 to reduce LDL cholesterol in people who don’t achieve LDL goals on standard medication, including those with familial hypercholesterolemia. The PCSK9 inhibitor won an expanded indication for the reduction of cardiovascular risk in 2017.

More recently, bempedoic acid (Nexletol) hit the market as an adjunct to maximally tolerated statin therapy for LDL reduction. As an oral drug, it could be an attractive alternative to the costly PCSK9 inhibitors, Eckel suggested.

HAUSER-RCT was a phase III trial that randomized 157 pediatric HeFH patients 2:1 to monthly evolocumab 420 mg injections or placebo. Study participants remained on background lipid-lowering therapy (79% on high- or moderate-intensity statins, and 13% on ezetimibe).

Mean age in the cohort was 13.7, and 56% were girls. The group was 85% white, which may limit the generalizability of the findings, Gaudet and colleagues acknowledged.

Nearly all patients received the full course of their assigned treatments.

There were “no safety concerns” for evolocumab given the similar incidence of adverse events between groups (62% vs 64% with placebo). The medication was associated with numerically greater rates of headache, oropharyngeal pain, flu, flu-type illness, upper respiratory tract infection, and constipation.

“The relatively short duration of the trial precluded the assessment of the effects of evolocumab on carotid intima-media thickness, neurocognition, and growth and development,” according to Gaudet’s team. “The long-term safety and efficacy of evolocumab in the management of familial hypercholesterolemia in pediatric patients will require further study.”

An open-label extension study, HAUSER-OLE, is ongoing.

In the TAUSSIG study, evolocumab was shown to be well tolerated over 4 years in young patients with severe HeFH or homozygous familial hypercholesterolemia.