Evinacumab hits mark in difficult-to-treat children with rare lipid disorder

The angiopoietin-like 3 inhibitor evinacumab appears to reduce low-density lipoprotein cholesterol (LDL-C) levels in children with homozygous familial hypercholesterolemia (HoFH) and persistently high LDL-C despite optimized therapy.

In a phase 3, part B, open-label study, LDL-C levels decreased by 48.3 percent from baseline through week 24 (mean absolute change, –131.9 mg/dL) with the addition of evinacumab to background lipid-lowering therapy. Evinacumab was administered intravenously at 15 mg/kg every 4 weeks. [Circulation 2024;149:343-353]

“LDL-C reductions from baseline occurred rapidly and were consistent from week 1 to week 24,” with the magnitude similar to the 49-percent decrease seen at week 24 in a phase 3 study involving adolescent and adult patients with HoFH, the investigators noted. [N Engl J Med 2020;383:711-720]

Most children (78.6 percent) achieved a ≥50-percent reduction in LDL-C at week 24. Subgroup analyses showed that the LDL-C decrease achieved with evinacumab did not differ by sex, race, ethnicity, baseline apheresis status, imputed LDLR activity, whether baseline LDL-C values were above or below the median values, apheresis status, and lomitapide treatment.

Aside from LDL-C, reductions were also seen in apolipoprotein B (apoB, –41.3 percent), nonhigh-density lipoprotein cholesterol (non–HDL-C, –48.9 percent), total cholesterol (–49.1 percent), and lipoprotein (a) (Lp[a], –37.3 percent).

Safety

The analysis included 14 children (mean age 9.1 years, 57.1 percent girls) with genetically proven HoFH (true homozygotes and compound heterozygotes). The median baseline LDL-C level was 263.7 mg/dL despite optimized lipid-lowering therapy. All patients had been receiving nonstatin lipid-lowering therapies, 85.7 percent were also on a statin, and half were undergoing lipoprotein apheresis.

Ten children (71.4 percent) had treatment-emergent adverse events. But of the recorded events, only nausea and abdominal pain were deemed to be treatment-related. A case of serious treatment-emergent adverse event of tonsillitis occurred, but this was unrelated to treatment.

“Overall, evinacumab was generally well-tolerated in these young paediatric patients with HoFH, and its safety profile was consistent with that observed in adult and adolescent patients. Immunogenicity potential was minimal: only one patient developed treatment-emergent antidrug antibodies, with a low titre, and no neutralizing antibodies were detected,” the investigators pointed out.

FDA-approved

“Until now, limited treatment options were available to help paediatric patients with HoFH. Recently, evinacumab … was approved by the US Food and Drug Administration (FDA) as an adjunct to other lipid-lowering therapies to treat patients 5 to 11 years of age with HoFH,” the investigators noted.

Despite the presence of limitations such as the open-label design, the relatively short follow-up period, and the small sample size, the present study showed that the evinacumab was efficacious for these extremely high-risk and difficult-to-treat young patients with HoFH and may, in turn, aid in the achievement of recommended LDL-C levels much earlier in the course of this rare disease, according to the investigators.