SEBELIPASE ALFA IN CHILDREN AND ADULTS WITH LYSOSOMAL ACID LIPASE DEFICIENCY: FINAL RESULTS OF THE ARISE STUDY.

BACKGROUND & 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. We report final results of 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 phase, 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 (range) age at randomization was 13 (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 (interquartile range) percent changes in lipid levels included a 25% (39%, 6.5%) reduction in low-density lipoprotein cholesterol and a 27% (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.

LAY SUMMARY: Sebelipase alfa is used to treat lysosomal acid lipase deficiency (LAL-D), a rare, inherited disease of lipid metabolism. We report the final results of the phase 3 ARISE clinical study, which show that replacement of the defective LAL enzyme with sebelipase alfa for up to 5 years allows adults and children 4 years of age and older to maintain their initial improvements in liver and cholesterol parameters over the long term, without worsening of liver disease.

CLINICAL TRIAL NUMBER: NCT01757184; EudraCT Number: 2011-002750-31.