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N Engl J Med. 2015 Sep 10;373(11):1010-20. doi: 10.1056/NEJMoa1501365.

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency.

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From the Northwestern University Feinberg School of Medicine and the Ann and Robert H. Lurie Children's Hospital, Chicago (B.K.B.); Icahn School of Medicine, Mount Sinai, New York (M.B.), and Women and Children's Hospital of Buffalo, Buffalo (R.E.) - both in New York; Centre Hospitalier Universitaire Brabois-Hôpital d'Enfants, Vandoeuvre-lès-Nancy (F.F.), and University Hospital Necker-Enfants Malades and Imagine Institute, Paris (V.V.) - both in France; University Hospital Center Zagreb and University of Zagreb, School of Medicine, Zagreb, Croatia (I.B.); Cincinnati Children's Hospital Medical Center, Cincinnati (T.A.B.); Hospital Universitario La Paz, Madrid (C.C.G.); Ege University Medical Faculty, Izmir (M.C.), and Gazi University Medical Faculty, Ankara (F.E.) - both in Turkey; Hospital Infantil de México Federico Gómez, Mexico City (A.C.-S.); Cambridge University Hospitals, Cambridge, United Kingdom (P.D.); Unit of Rare Diseases, Department of Pediatrics, Gaslini Institute, Genoa (M.D.R.), and University of Padua, Padua (M.S.) - both in Italy; Stanford University, Palo Alto (G.M.E.), and University of California, San Francisco, San Francisco ( J.K.) - both in California; Children's Hospital of Philadelphia, Philadelphia (C.F.); Alfred I. duPont Hospital for Children, Wilmington, DE (K.N.F.); University of Arizona Cancer Center, Tucson (C.L.); Villa Metabolica, Center of Pediatric and Adolescent Medicine, University of Mainz, Mainz (E.M.), and University Hospital Freiburg, Freiburg (K.O.S.) - both in Germany; Boston Children's Hospital, Boston (E.G.N.), and Synageva BioPharma, Lexington (Y.Y., S.E., S.R.-C., A.G.Q.) - both in Massachusetts; John Hunter Children's Hospital, and Discipline of Paediatrics and Child Health, University of Newcastle, Newcastle, NSW (S.N.), Royal Children's Hospital, Parkville, VIC (H.P.), and Royal Brisbane and Women's Hospital, Brisbane, QLD (M.W.) - all in Australia; Faculty Hospital, Palacky University, Olomouc, Czech Republic



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.


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.


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.


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 number, NCT01757184.).

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