Sebelipase alfa in children and adults with lysosomal acid lipase deficiency: Final results of the ARISE study

Abstract

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 from the phase III 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 (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 (IQR) 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.

Clinical trial number: NCT01757184; EudraCT Number: 2011-002750-31 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 III 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.

Keywords: dyslipidemia; enzyme replacement therapy; liver; lysosomal storage disease; transaminases.

Conflict of interest statement

Conflict of interest B. K. Burton has received funding for the conduct of clinical studies from Alexion, AstraZeneca Rare Disease, BioMarin, Shire (Takeda), Genzyme, Ultragenyx, Homology Medicines, Denali, and Sangamo; funding for independent research from BioMarin and Shire; and consulting fees and honoraria from BioMarin, Shire (Takeda), Alexion, AstraZeneca Rare Disease, Genzyme, Horizon, JCR Pharma, Moderna, Aeglea, Agios, Denali, Ultragenyx, Regenxbio, Applied Therapeutics, and Inventiva. F. Feillet and M. Balwani are members of the International LAL-D Registry Scientific Advisory Board and have received honoraria for participation in advisory boards and funding from Alexion, AstraZeneca Rare Disease. K. N. Furuya has received consulting fees and honoraria from Alexion, AstraZeneca Rare Disease. S. Marulkar is an employee of and may own stock/have stock options in Alexion, AstraZeneca Rare Disease. Please refer to the accompanying ICMJE disclosure forms for further details.

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