Lomitapide in Pediatric Patients with Homozygous Familial Hypercholesterolemia – Analysis of Secondary and Safety Endpoints from the APH-19 Study

Background/Synopsis

Homozygous familial hypercholesterolemia (HoFH) is characterized by mutations in the low-density lipoprotein (LDL) receptor leading to highly elevated levels of LDL-cholesterol (LDL-C). As a result, patients with HoFH develop atherosclerotic cardiovascular disease in childhood and have a low life expectancy of ∼18 years without appropriate treatment. Diagnosis in early childhood is essential to reduce morbidity and mortality. Lomitapide is a selective microsomal triglyceride transfer protein inhibitor approved for adults with HoFH that works independently of the LDL receptor to lower LDL-C. APH-19 (NCT04681170) is the first clinical trial of lomitapide in pediatric patients with HoFH and met its primary endpoint (LDL-C reduction of -53.5% at Week 24; p<0.0001).

Objective/Purpose

We report additional parameters from APH-19 relating to the efficacy and safety of lomitapide in pediatric patients.

Methods

APH-19 is a phase 3, open-label, single-arm clinical trial in HoFH patients aged 5–17 years (N=43) consisting of a run-in period followed by 24-week efficacy and 80-week safety phases. Patients were stratified by age into three dose escalation groups, where the maximum doses were 20, 40 and 60 mg. Here, additional data at Week 24 of patient-level LDL-C reductions, lipoproteins (apolipoprotein B [ApoB] and lipoprotein A [Lp(a)]) and additional safety endpoints (growth/maturation and fat-soluble vitamin levels) are reported.

Results

Lomitapide treatment resulted in up to a 95% reduction of LDL-C from baseline at Week 24 with 53.5% of patients (n=23) having >50% reduction in LDL-C from baseline (Figure). Mean reduction in ApoB was -52.4% at Week 24 (p<0.0001); an ApoB subgroup analysis indicated general consistency across a range of parameters. Mean change from baseline in Lp(a) was -23.6% (p=0.0030) for nmol/L methodology and -11.3% (p=0.2884, Fisher Combined p-value p=0.0070) for mg/dL analysis. Subgroup results will be presented.

There were no clinically significant mean changes in weight or height from Baseline to Week 24. The mean change in weight-for-age Z-score was -0.371 for patients aged 5–10 years (11–17, N/A). Changes in height-for-age Z-score were -0.064 and -0.060 for patients aged 5–10 and 11–17 years, respectively. Fat-soluble vitamins at Week 24 were within normal range for individuals aged 5–17 years; vitamin E increased in 10.0% of patients aged 5–10 years, considered mild in severity.

Conclusions

These data further support the efficacy and safety of lomitapide across various parameters in pediatric patients. The lack of impact on patient maturation endpoints is encouraging; however, further long-term data are required.