MANNHEIM, Germany — Lomitapide, which reduces lipoprotein production in the liver, could help manage pediatric homozygous familial hypercholesterolemia (HoFH), suggest results of a trial that showed large reductions in circulating lipids.
The research was presented May 23 at the 91st European Atherosclerosis Society (EAS) Congress.
Lomitapide inhibits microsomal triglyceride transfer protein, which plays a key role in apolipoprotein B-containing lipoprotein assembly and secretion in the liver and intestines. Crucially, the drug acts independently of the LDL cholesterol receptor.
It was approved in December 2012 by the US Food and Drug Administration for use in adults with HoFH, sold under the name Juxtapid, and by the European Medicines Agency, where the brand name is Lojuxta.
The current trial involved more than 40 children and teenagers with HoFH aged 5-17 years; they were treated with the drug for 24 weeks, resulting in reductions of low density lipoprotein (LDL) cholesterol of almost 54%, with nearly 42% reaching target levels.
The drug was also associated with marked reductions in other key lipids of at least 50%. However, 67% of patients also experienced gastrointestinal adverse events, and around 25% saw their levels of liver enzymes increase.
Early Diagnosis "Imperative"
The findings show that the "early diagnosis and treatment of HoFH is imperative," said study presenter Luis Masana, MD, PhD, director of the Vascular Medicine and Metabolism Unit at 'Sant Joan de Reus' University Hospital, Tarragona, Spain.
"I think that, with these results, we are bringing a new hope for this group of patients," he continued. "I also think we will increase the quality of life not just of the patients but also all the families involved in [managing] this problem."
Session co-chair Andreas Zirlik, MD, PhD, head of the Department of Cardiology and chairman of the University Heart Center Graz, LKH-University Hospital and Medical University of Graz, Graz, Austria, was more circumspect in his appraisal of the results.
He told theheart.org | Medscape Cardiology that it is "always very difficult to establish therapy in pediatrics," and believes that the drug "will give us an additional option" in managing HoFH.
However, Zirlik warned that he is a "little bit concerned" about lomitapide's adverse event profile, and "I would need to see a little bit deeper into the safety data."
Highlighting the elevations in liver enzymes of around 25%, he asked: "What does it mean?" And how will it "play out in the long run?"
Beyond lomitapide, Zirlik pointed out that there are other drugs that have shown potential in managing HoFH and could potentially be used in the pediatric population, such as angiopoietin-like 3 protein (ANGPTL3) inhibitors and small interfering RNA (siRNA) compounds that target upstream production. "So, let's see how they pan out," he said.
HoFH is an "ultra-rare, life-limiting condition," with an estimated prevalence of approximately 3 per 1 million people, and a life expectancy in untreated patients of just 18 years, Masana said during his presentation.
Case series of lomitapide use in pediatric HoFH patients have shown encouraging results that are consistent with those seen in adults, he noted, with many able to achieve their LDL cholesterol target and stop or reduce apheresis.
To investigate further, a phase 3, single arm, open-label study was conducted. Following screening, 46 children and teenagers with HoFH underwent a 6- to 12-week run-in period, during which they were put on a low-fat diet with nutritional supplements.
"As you can imagine," Masana said, "we are reducing the capacity for fat absorption with lomitapide, so the supplements and low-fat diet are necessary."
Of these, 43 participants then entered a 24-week treatment period in which they were started on one of three doses, before undergoing dose escalation to the maximally tolerated dose. This was followed by an 80-week open-label safety phase, in which they continued on the maximally tolerated dose, and then a follow-up period.
For the current presentation, Masana focused on the efficacy phase, showing that the mean age of participants was 10.7 years, and that 55.8% were female. The HoFH diagnosis was confirmed genetically in 88.4% of cases.
Results showed that lomitapide was associated with a significant reduction in LDL cholesterol levels, from 435.8 mg/dL at baseline to 176.5 mg/dL at Week 24, which corresponded to a 53.5% overall reduction (P < .0001).
This meant that 41.9% of patients achieved their EAS LDL cholesterol target of <135 mg/dL at some point during the 24-week treatment period.
Stratifying by age, the reduction between baseline and Week 24 was 538.5 mg/dL to 207.2 mg/dL, or 56.5%, in the 20 children aged 5-10 years, and 346.5 mg/dL to 149.9 mg/L, or 50.9%, in the 23 patients aged 11-17 years.
Masana explained that the results were "a little bit better in the younger group because they were receiving less treatment at this stage of the disease" than the older group.
He showed that lomitapide was associated with significant reductions in other lipid markers, including a 53.9% reduction in non–HDL cholesterol (P < .0001), a 50.1% drop in total cholesterol (P < .0001), and a 50.2% fall in very-low-density lipoprotein cholesterol (P < .0001).
Results showed 93% of patients experienced treatment-related adverse events, with 11.6% having serious events, and 4.7% having events that led to study discontinuation. There was one (2.3%) major adverse cardiac event, but no deaths.
He said that, despite these figures, the adverse events were "mostly mild or moderate."
The majority (67%) of patients nevertheless had gastrointestinal adverse events, which were, "in general, associated with a lack of adherence to the low-fat diet."
Aspartate aminotransferase levels were elevated in 23% of patients, while 28% had elevations in alanine aminotransferase, which were described by Masana as "moderate."
The study was sponsored by Amryt Pharma. Masana declares relationships with Amarin, Amryt, Daiichi-Sankyo, Novartis, Sanofi, Servier, Servier, and Viatrix.
European Atherosclerosis Society (EAS) 2023: Abstract 1493.
Presented May 23, 2023.
Lead image: Alexander Egizarov/Dreamstime
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Cite this: Lomitapide Shows Promise in Pediatric Homozygous FH - Medscape - May 29, 2023.