Sebelipase alfa over 52weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

Abstract

Background and aims Lysosomal Acid Lipase Deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. Methods Sebelipase alfa (1 mg/kg or 3 mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. Results 216 infusions were administered to eight adult subjects through Week 52 during LAL-CL04. At Week 52, mean alanine aminotransferase and aspartate aminotransferase were normal with mean change from baseline of −58% and −40%. Mean change for low density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were −60%, −39%, −36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. Conclusions Long-term dosing with sebelipase alfa in Lysosomal Acid Lipase-Deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

Epidemiological modifiers of non-alcoholic fatty liver disease: Focus on high-risk groups

“…156 Definite diagnosis of this lysosomal storage disease, which requires demonstration of a significantly deficient LAL activity followed by molecular sequencing of the LIPA gene, 157 has major clinical consequences given that enzyme replacement therapy with sebelipase alfa is safe and effective. 158,159 Based on studies showing that hypertriglyceridemia is the most common feature and is an independent predictor of NAFLD, [160][161][162][163][164] we recommend that hypertriglyceridemic should invariably undergo liver ultrasonagraphy. In particular, mixed hyperlipidemia associated with raised ALT accurately predicts NAFLD.…”

New Pyripyropene A Derivatives, Highly SOAT2-Selective Inhibitors, Improve Hypercholesterolemia and Atherosclerosis in Atherogenic Mouse Models

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The Disease Is the Accumulation of Cholesterol Esters Due to Deficit of Lysosomal Acid Lipase. Clinical Case of Lysosomal Acid Lipase Deficiency Is Described in This Article

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