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For kids with heterozygous familial hypercholesterolemia (HeFH) uncontrolled by statins, adding alirocumab (Praluent) reduced low-density lipoprotein cholesterol (LDL-C), a randomized clinical trial showed.

The PCSK9 inhibitor significantly reduced LDL-C compared with placebo in both of two cohorts studied at 24 weeks, reported Raul Santos, MD, PhD, of the University of Sao Paulo Medical School Hospital in Brazil, and colleagues in .

The least squares (LS) mean reduction from baseline over placebo was 43.3% in the cohort dosed every 2 weeks and 33.8% in the cohort dosed every 4 weeks, which were both significant at P<0.001.

Some pediatric patients cannot achieve LDL-C targets despite high-dose statins or multiagent lipid-lowering therapies (LLTs), Santos and colleagues noted. "Additional LLTs are needed for these patients to help control LDL-C concentrations and reduce risk of atherosclerotic disease in adulthood," they wrote.

Monoclonal antibodies targeting PCSK9 have been shown to reduce LDL-C and other atherogenic lipoproteins in adults with hyperlipidemia, including those with HeFH. Evolocumab (Repatha) gained an indication for treatment of pediatric FH as well based on a showing 38.3 percentage points more LDL-C reduction than with placebo when given monthly.

A prior phase II dose-finding study in children and adolescents suggested the same would be true with alirocumab, "consistent with reductions reported in adults, supporting further investigation in pediatric HeFH," Santos and colleagues added.

The new phase III results fill three knowledge gaps, Santos told 番茄社区 in an email.

"One, we can start treating children as young as 8 years old (there was previous for kids [10 years of age and older])," he wrote. "Two, we add the possibility to treat with different regimens (every 2 or 4 weeks). Three, we have shown for the first time that PCSK9 inhibition in pediatric patients reduces not only LDL-C but also the pro-atherogenic lipoprotein(a)."

Among the significant reductions versus placebo through hierarchical testing of the first 12 secondary endpoints studied, there were significant -15.2% and -24.9% differences in the adjusted mean percentage change of lipoprotein(a) with dosing every 2 and 4 weeks, respectively.

The trial included 153 patients ages 8 to 17 years with HeFH and LDL-C of 130 mg/dL or greater despite statins or other LLTs who were randomized 2:1 to alirocumab or placebo. It was conducted from May 2018 through August 2022 at 43 facilities in 24 countries.

About 95% of patients in both the cohort dosed every 2 weeks and the cohort dosed every 4 weeks completed the double-blind period.

LDL-C less than 130 mg/dL was achieved by 77.3% of patients receiving alirocumab in the cohort dosed every 2 weeks and 76.3% of patients receiving it every 4 weeks. And 21.6% in the 2-week cohort and 32.4% in the 4-week cohort achieved LDL-C reduction of 50% or greater.

Beyond the 24-week double-blind period, an 80-week open-label period showed LDL-C reductions were "well maintained in patients who received alirocumab during the double-blind period, while those who switched from placebo to alirocumab had reductions in LDL-C at week 32 that were maintained through week 104," Santos and colleagues further noted.

The LS mean change in LDL-C from baseline to week 104 was −26.3% in the cohort dosed every 2 weeks and −23.9% in the cohort dosed every 4 weeks.

At week 104, 63.7% of patients in the 2-week cohort and 59.6% of patients in the 4-week cohort achieved LDL-C less than 130 mg/dL, while 13.8% of patients in the 2-week cohort and 21.1% in the 4-week cohort achieved LDL-C reduction of 50% or greater.

Serious adverse events (SAEs) were reported in four patients receiving alirocumab versus one patient receiving placebo in the cohort dosed every 2 weeks as well as two patients receiving alirocumab versus one receiving placebo in the cohort dosed every 4 weeks. Most SAEs were reported as resolved or recovered at the end of the double-blind period.

Two cases of syncope with alirocumab dosed every 4 weeks were deemed treatment related, and one of these led to treatment discontinuation. Another patient discontinued treatment due to a non-serious disturbance in attention and memory.

Potential limitations included the relatively small sample size in the trial, the overwhelmingly white trial population, statin doses below the maximal approved in most participants, and the potential for variability in protocol adherence inherent to using different sites.

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