A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency

Barbara K. Burton, Manisha Balwani, Francois Feillet, Ivo Baric, T. Andrew Burrow, Carmen Camarena Grande, Mahmut Coker, Alejandra Consuelo-Sanchez, Patrick Deegan, Maja Di Rocco, Gregory M. Enns, Richard Erbe, Fatih Ezgu, Can Ficicioglu, Katryn N. Furuya, John Kane, Christina Laukaitis, Eugen Mengel, Edward G. Neilan, Scott NightingaleHeidi Peters, Maurizio Scarpa, K. Otfried Schwab, Vratislav Smolka, Vassili Valayannopoulos, Marnie Wood, Zachary Goodman, Yijun Yang, Stephen Eckert, Sandra Rojas-Caro, Anthony G. Quinn

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

Abstract

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.)

Original languageEnglish (US)
Pages (from-to)1010-1020
Number of pages11
JournalNew England Journal of Medicine
Volume373
Issue number11
DOIs
StatePublished - Sep 10 2015

ASJC Scopus subject areas

  • Medicine(all)

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