Lomitapide Effective in Lowering LDL Cholesterol in Children with Homozygous Familial Hypercholesterolemia: APH-19 Study

The multicenter, open-label trial, APH-19, revealed significant reductions in LDL cholesterol levels, offering a promising new option for managing this challenging condition in children.

HoFH is characterized by genetic mutations that hinder the ability of the body to process cholesterol effectively, often resulting in severe cardiovascular complications at a young age. Traditional treatments, such as statins, may not provide adequate relief due to the unique metabolic challenges faced by these patients, making alternative therapies crucial.

Lomitapide is an orally administered inhibitor of microsomal triglyceride transfer protein (MTP) that effectively reduces LDL cholesterol levels and is approved for use in adults with homozygous familial hypercholesterolemia. Considering this, Prof Luis Masana, Sant Joan University Hospital, CIBERDEM, Reus, Spain, and colleagues sought to evaluate the efficacy and safety of lomitapide in pediatric patients with HoFH who were receiving standard lipid-lowering therapy.

For this purpose, the researchers conducted the APH-19 trial, an open-label, single-arm phase 3 study at 12 centers in Germany, Israel, Italy, Saudi Arabia, Spain, and Tunisia. Following a 6-week run-in period, the trial included a 24-week efficacy phase and an 80-week safety phase. Patients aged 5 to 17 with diagnosed HoFH, already on stable lipid-lowering therapy, were given oral lomitapide, starting at 2 mg for younger patients and 5 mg for older ones.

The primary endpoint was the change in LDL cholesterol from baseline to week 24, while secondary outcomes included changes in total cholesterol, triglycerides, and other lipid markers. Safety was evaluated in all patients who received the drug.

The findings from the study are as follows:

• Between December 20, 2020, and October 16, 2022, 43 patients were treated, including 56% females, with a median age of 10.7 years.
• The mean change in LDL cholesterol from baseline at week 24 was a reduction of 53.5%.
• At week 24, mean percentage reductions included:
  • Non-HDL cholesterol: –53.9%
  • Total cholesterol: –50.0%
  • VLDL cholesterol: –50.2%
  • Apolipoprotein B: –52.4%
  • Triglycerides: –49.9%
  • Lipoprotein(a): –11.3% (in 21 patients, measured in mg/dL), and –23.6% (in 22 patients, measured in nmol/L).
• Adverse events were generally mild, primarily gastrointestinal and hepatic.
• Adverse events of special interest were reported in five patients, with gastrointestinal issues in two and hepatic issues in three.
• One serious treatment-emergent adverse event occurred, characterized by a rise in hepatic enzymes, leading to two dose interruptions, two dose reductions, and one repeated dose escalation.

"Lomitapide resulted in a substantial and clinically significant reduction in LDL cholesterol levels, offering a promising LDL receptor-independent treatment option for pediatric patients with homozygous familial hypercholesterolemia," the researchers concluded.

Reference:

DOI:10.1016/S2213-8587(24)00277-8