medwireNews: Pediatric patients with homozygous familial hypercholesterolemia (HoFH) experience clinically significant reductions in low-density lipoprotein (LDL) cholesterol when given the microsomal triglyceride transfer protein (MTP) inhibitor lomitapide, research shows.
Writing in The Lancet Diabetes & Endocrinology, Luis Masana (Universitat Rovira i Virgili, Reus, Spain) and co-authors explain that although the European Atherosclerosis Society (EAS) “have acknowledged that lomitapide has potential as a paediatric treatment,” data on its efficacy and safety were “scarce in children with HoFH.”
They say that the findings from the current phase 3, APH-19 trial “bridge the gap in terms of showing lomitapide to be both acceptably tolerated and efficacious in patients aged 5 years or older.”
The single-arm trial included 43 patients aged 5 to 17 years (median 10.7 years, 56% female) who were receiving standard-of-care lipid-lowering therapy for HoFH. This was supplemented with oral lomitapide at a starting dose of 2 mg once daily in patients younger than 15 years old, and 5 mg once daily in those aged 16–17 years. This was then increased every 4 weeks to the maximum tolerated dose.
Masana et al report that, at week 24, LDL cholesterol levels had fallen by a mean of 53.5%, from a mean of 435.8 mg/dL (11.3 mmol/L) at baseline to 176.5 mg/dL (4.6 mmol/L) at week 24.
They say that this “degree of LDL cholesterol reduction is marked in the context of a cohort that was receiving maximally tolerated statin or ezetimibe lipid-lowering therapy, with use of lipoprotein apheresis widespread among the cohort (44% at baseline).”
In an accompanying comment, Liam Brunham (University of British Columbia, Vancouver, Canada) and Robert Hegele (Western University, London, Ontario, Canada) note that this reduction “would be expected to translate into meaningful reductions in cardiovascular morbidity and mortality.”
Furthermore, at any time up to week 24, 42% of patients reached the prespecified EAS-recommended target LDL cholesterol concentration of less than 135 mg/dL (3.5 mmol/L) and 37% reached the updated recommended EAS target LDL cholesterol concentration of less than 115 mg/dL (3.0 mmol/L)
The participants also experienced significant mean percentage reductions from baseline to week 24 in non-high-density lipoprotein cholesterol (53.9%), apolipoprotein B (52.4%), very LDL cholesterol (50.2%), total cholesterol (50.0%), triglycerides (49.9%), and lipoprotein(a) (11.3% in 21 patients with measurements in mg/dL; 23.6% in 22 patients with measurements in nmol/L).
Finally, the researchers observed that safety outcomes “aligned with studies of lomitapide in adults with HoFH.”
Over half (58%) of participants had at least one treatment-emergent adverse event, and these were generally mild or moderate and of a gastrointestinal or hepatic nature. Diarrhea occurred in 47% of participants, abdominal pain in 42%, and increased hepatic enzymes in 37%. Serious hepatotoxicity occurred in one patient, resulting in two dose interruptions, two dose reductions, and a repeated dose escalation.
There were no significant changes in weight, height, BMI, or Tanner stage during the 24-week efficacy phase of the study.
Masana and co-authors conclude: “Lomitapide provides an LDL [receptor]-independent treatment option that might help to address the considerable unmet needs present in this highly vulnerable patient group, helping them to reach recommended target LDL cholesterol concentrations.”
Brunham and Hegele echo this conclusion, saying that “[t]he APH-19 trial provides important new data regarding the efficacy and safety of lomitapide in the treatment of HoFH in children.”
They add: “The incremental 53.5% reduction in LDL cholesterol achieved on a background of high-intensity statin, ezetimibe, and common lipoprotein apheresis use is impressive and clinically significant.”
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Lancet Diabetes Endocrinol 2024; doi:10.1016/S2213-8587(24)00233-X
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