BACKGROUND: Lysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile. RESULTS: Substantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of -58 U per liter versus -7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment. CONCLUSIONS: Sebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.).

From the Northwestern University Feinberg School of Medicine and the Ann and Robert H Lurie Children's Hospital Chicago all in Australia; Faculty Hospital Palacky University Olomouc Czech Republic

N Engl J Med. 2015 Sep 10;373(11):1071-3. doi: 10.1056/NEJMe1509055. PubMed

Nat Rev Cardiol. 2015 Dec;12(12):683. doi: 10.1038/nrcardio.2015.154. PubMed

Nat Rev Endocrinol. 2015 Dec;11(12):696-7. doi: 10.1038/nrendo.2015.182. PubMed

J Hepatol. 2022 Mar;76(3):501-502. doi: 10.1016/j.jhep.2021.12.002. PubMed

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Sebelipase alfa for lysosomal acid lipase deficiency: 5-year treatment experience from a phase 2 open-label extension study

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NCT01757184