Liver and Bile
J Hepatol. 2022;76(3):577–87
Sebelipase alfa in children and adults with lysosomal acid lipase deficiency: Final results of the ARISE study
Background and aims: Children and adults with lysosomal acid lipase deficiency (LAL-D) experience cirrhosis and dyslipidemia from lysosomal accumulation of cholesteryl esters and triglycerides. Sebelipase alfa enzyme replacement therapy is indicated for individuals with LAL-D. The authors report final results from the phase 3 randomized ARISE study of sebelipase alfa in children aged ≥ 4 years and adults with LAL-D.
Methods: The study included a 20-week, double-blind, placebo-controlled period; a 130-week, open-label, extension period; and a 104-week, open-label, expanded treatment period. In the open-label periods, all patients received intravenous sebelipase alfa every other week. The primary outcome was alanine aminotransferase (ALT) level normalization; aspartate aminotransferase (AST) levels, lipid parameters, liver histology, liver and spleen volume and fat content, and safety were also assessed.
Results: Of 66 patients enrolled, 59 completed the study. Median age at randomization was 13 (range, 4.7–59) years. At the last open-label visit, ALT and AST levels had normalized in 47% and 66% of patients, respectively. Patients who switched from placebo to sebelipase alfa experienced sustained improvements in ALT and AST during the open-label periods that mirrored those observed in the sebelipase alfa group during the double-blind period. Median percent changes in lipid levels included a 25% (interquartile range [IQR], 39–6.5%) reduction in low-density lipoprotein cholesterol and a 27% (IQR, 19–44%) increase in high-density lipoprotein cholesterol. Most adverse events during the open-label periods were mild to moderate in severity; 13 patients had infusion-associated reactions (serious in 1 patient). Six patients (9%) developed anti-drug antibodies.
Conclusions: Early and rapid improvements in markers of liver injury and lipid abnormalities with sebelipase alfa were sustained, with no progression of liver disease, for up to 5 years.