Study Proves Effectiveness of Ezetimibe in Lysosomal Diseases


Results from an observational case series published in the Orphanet Journal of Rare Diseases conclude that ezetimibe can be an effective, safe, and sustainable treatment option for LAL-D.

Results from an observational case series published in the Orphanet Journal of Rare Diseases conclude that ezetimibe can be an effective, safe, and sustainable treatment option for lysosomal acid lipase deficiency (LAL-D).

Maja Di Rocco, M.D, of the Department of Pediatrics, Unit of Rare Diseases, Giannina Gaslini Institute, Genoa, Italy served as the lead researcher on the study, and found that all patients enrolled found a significant reduction of alanine aminotransferase, cholesterol and triglyceride.

In patients with autosomal recessive disease, a mutation in the LIPA gene leads to the lack of the enzyme lysosomal acid lipase. Without it — or with insufficient amounts of it – fat is unable to be processed inside the lysosomes, leading to a buildup within the cells and tissues of the body. Symptoms can vary from patient to patient, based on how much of the enzyme is present. If the enzyme is entirely absent, symptoms, including severe liver and adrenal gland damage, begin in the first year of life.

When LAL-D presents in infants, it is commonly referred to as Wolman disease. It is characterized by a progressive course leading to death within the first year of life. The childhood/adult onset iteration of the condition is sometimes referred to as Cholesteryl Ester Storage Disease (CESD), and has a less severe clinical course.

For many years, the only therapeutic option for patients with LAL-D was liver transplantation because statin therapy was unable to prevent liver fibrosis progression and complete organ failure in patients was inevitable. Ezetimibe is an azetidine derivative that blocks Niemann Pick C1-like 1 (NPC1L1), a protein known for playing a pivotal role in intestinal cholesterol absorption and in enterohepatic circulation of cholesterol. It additionally has the potential to decrease plasmatic concentration of Low Density Lipoprotein and other apoB-containing lipoproteins that are the substrate of lysosomal acid lipase.

In the study, 2 patients with CESD were treated with ezetimibe for 9 years and a third patient was treated for 10 years. Treatment was added to a low dose of atorvastatin in the first 2 patients during the last 6 years. Because the study was an observational case series, no controls were included.

Patient 1 and Patient 2, twin sisters, were born from unrelated parents and no family history of dyslipidemia was reported. Patient 1 presented with hypercholesterolemia, severe hepatosplenomegaly, and hyperechoic liver on ultrasound, while mixed hyperlipidemia was present and enzyme assay and molecular analysis confirmed the diagnosis of LAL-D for patient 2. At the time of enrollment in the phase 3 sebelipase alpha trial, both had already been treated with ezetimibe, and their alanine aminotransferase (ALT) levels were less than 1.5 times the upper limit of what is considered normal.

Patient 3, who was also born from unrelated parents and did not have a family history of dyslipidemia reported, was diagnosed during evaluation for inguinal lymphadenopathy associated with increased hepatic transaminases and mild hepatosplenomegaly, unresponsive to anti-inflammatory and antibiotic treatment. Immediately after his diagnosis, he was treated with ezetimibe at a daily-dose of 10 mg/day for 10 years without the addition of statin. No adverse events (AE) were recorded, and no supplementary drugs were used.

The reduction of ALT levels served as the primary endpoint of the study, and all 3 subjects showed a reduction after 9 years of treatment in Patients 1 and 2, and 10 years of treatment in Patient 3. Additionally, a lessening of total cholesterol (TC) and triglycerides (TG), secondary endpoints, were observed.

The clinical outcome observed in patient 3, who was treated with ezetimibe alone, raises questions regarding whether there was further benefit in the addition of statin. Further studies are still required to exhibit that ezetimibe can serve as an alternative treatment to enzyme replacement therapy.

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Sources:1. Di Rocoo M, Pisciotta L, Madeo A, Bertamino A, Bertolini S. RLong term substrate reduction therapy with ezetimibe alone or associated with statins in three adult patients with lysosomal acid lipase deficiency. Orphanet Journal of Rare Diseases. 2018:13-24. doi: 10.1186/s13023-018-0768-8.

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