BACKGROUND & AIMS: Lysosomal acid lipase deficiency is an autosomal recessive enzyme deficiency resulting in lysosomal accumulation of cholesteryl esters and triglycerides. LAL-CL04, an ongoing extension study, investigates the long-term effects of sebelipase alfa, a recombinant human lysosomal acid lipase. METHODS: Sebelipase alfa (1mg/kg or 3mg/kg) was infused every-other-week to eligible subjects. Safety and tolerability assessments, including liver function, lipid profiles and liver volume assessment, were carried out at regular intervals. RESULTS: 216 infusions were administered to eight adult subjects through week 52 during LAL-CL04. At week 52, mean alanine aminotransferase and aspartate aminotransferase levels were normal with mean change from baseline of -58% and -40%. Mean changes for low-density lipoprotein, total cholesterol, triglyceride and high-density lipoprotein were -60%, -39%, -36%, and +29%, respectively. Mean liver volume by magnetic resonance imaging and hepatic proton density fat fraction decreased (12% and 55%, respectively). Adverse events were mainly mild and unrelated to sebelipase alfa. Infusion-related reactions were uncommon: three events of moderate severity were reported in two subjects; one patient's event was suggestive of a hypersensitivity-like reaction, but additional testing did not confirm this, and the subject has successfully re-started sebelipase alfa. Of samples tested to date, no anti-drug antibodies have been detected. CONCLUSIONS: Long-term dosing with sebelipase alfa in lysosomal acid lipase-deficient patients is well tolerated and produces sustained reductions in transaminases, improvements in serum lipid profile and reduction in the hepatic fat fraction. A randomized, placebo-controlled phase 3 trial in children and adults is underway (ARISE: NCT01757184).

Department of Genetics and Genomic Sciences The Mount Sinai School of Medicine New York NY United States

Department of Medicine Addenbrooke's Hospital Cambridge UK

Department of Pediatrics 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Pediatrics Lucile Packard Children's Hospital Stanford University Stanford CA United States

Divisions of Cardiology University of California San Francisco CA United States

Divisions of Endocrinology and Metabolism University of California San Francisco CA United States

Eureka Internal Medicine Eureka CA United States

Health Sciences North Sudbury Ontario Canada

Leeds Institute of Cancer and Pathology Leeds UK

Manchester Centre for Genomic Medicine St Mary's Hospital Manchester UK

Ref Centre IEM Necker Enf Malades Hosp IMAGINE Institute and Paris Descartes University Paris France

Salford Royal NHS Foundation Trust Salford UK

Synageva BioPharma Corp Lexington MA United States

University of California Davis Medical Center Department of Pediatrics Section of Genetics Davis CA United States

University of California San Diego CA United States

University of Minnesota Minneapolis MN United States

Zobrazit více v PubMed

Du H, Witte DP, Grabowski GA. Tissue and cellular specific expression of murine lysosomal acid lipase mRNA and protein. J Lipid Res. 1996;37:937–949. PubMed

Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl Ester Storage Disease: Review of the Findings in 135 Reported Patients with an Under-Diagnosed Disease. Journal of Hepatology. J Hepatol. 2013;58:1230–1243. PubMed

Grabowski G, Du H. Lysosomal Acid Lipase Deficiencies: The Wolman Disease/Cholesteryl Ester Storage Disease Spectrum. In: Beaudet A, Vogelstein B, Kinzler K, Antonarakis S, Ballabio A, editors. The Metabolic and Molecular Basis of Inherited Metabolic Disease (Online) 8th ed. New York: McGraw-Hill, Inc.; 2012.

Sloan HR, Fredrickson DS. Enzyme deficiency in cholesteryl ester storage disease. J Clin Invest. 1972;51:1923–1926. PubMed PMC

Beaudet AL, Ferry GD, Nichols BL, Jr, Rosenberg HS. Cholesterol ester storage disease: clinical, biochemical, and pathological studies. J Pediatr. 1977;90:910–914. PubMed

Cagle PT, Ferry GD, Beaudet AL, Hawkins EP. Pulmonary hypertension in an 18-year-old girl with cholesteryl ester storage disease (CESD) Am J Med Genet. 1986;24:711–722. PubMed

Gasche C, Aslanidis C, Kain R, Exner M, Helbich T, Dejaco C, et al. A novel variant of lysosomal acid lipase in cholesteryl ester storage disease associated with mild phenotype and improvement on lovastatin. J Hepatol. 1997;27:744–750. PubMed

Chatrath H, Keilin S, Attar BM. Cholesterol ester storage disease (CESD) diagnosed in an asymptomatic adult. Dig Dis Sci. 2009;54:168–173. PubMed

Elleder M, Chlumská A, Hyánek J, Poupetová H, Ledvinová J, Maas S, et al. Subclinical course of cholesteryl ester storage disease in an adult with hypercholesterolemia, accelerated atherosclerosis, and liver cancer. J Hepatol. 2000;32:528–534. PubMed

Ambler GK, Hoare M, Brais R, Shaw A, Butler A, Flynn P, et al. Orthotopic liver transplantation in an adult with cholesterol ester storage disease. JIMD Rep. 2013;8:41–46. PubMed PMC

Scott SA, Liu B, Nazarenko I, Martis S, Kozlitina J, Yang Y, et al. Frequency of the cholesteryl ester storage disease common LIPA E8SJM mutation (c.894G>A) in various racial and ethnic groups. Hepatology. 2013;58:958–965. PubMed PMC

Marshall WC, Ockenden BG, Fosbrooke AS, Cumings JN. Wolman's disease. A rare lipidosis with adrenal calcification. Arch Dis Child. 1969;44:331–341. PubMed PMC

Konno T, Fujii M, Watanuki T, Koizumi K. Wolman's disease: the first case in Japan. Tohoku J Exp Med. 1966;90:375–389. PubMed

Crocker AC, Vawter GF, Neuhauser EB, Rosowsky A. Wolman's disease: three new patients with a recently described lipidosis. Pediatrics. 1965;35:627–640. PubMed

Leavitt M, Burt AD, Hu W, Canty D, Gray M, Bray A, et al. Recombinant lysosomal acid lipase normalized liver weight, transaminases and histopathological abnormalities in an in vivo model of cholesterol storage ester disease. J Hepatol. 2011;54(Supplement 1):S358.

Levy R, Ostlund RE, Jr, Schonfeld G, Wong P, Semenkovich CF. Cholesteryl ester storage disease: complex molecular effects of chronic lovastatin therapy. J Lipid Res. 1992;33:1005–1015. PubMed

Balwani M, Breen C, Enns GM, Deegan PB, Honzík T, Jones S, et al. Clinical effect and safety profile of recombinant human lysosomal acid lipase in patients With cholesteryl ester storage disease. Hepatology. 2013;58:950–957. PubMed PMC

Hamilton G, Yokoo T, Bydder M, Cruite I, Schroeder ME, Sirlin CB, et al. In vivo characterization of the liver fat 1H MRspectrum. NMR Biomed. 2011;24:784–790. PubMed PMC

Kang GH, Cruite I, Shiehmorteza M, Wolfson T, Gamst AC, Hamilton G, et al. Reproducibility of MRI-Determined Proton Density Fat Fraction Across Two Different MR Scanner Platforms. J Mag Res Imag. 2011;34:928–934. PubMed PMC

Yokoo T, Shiehmorteza M, Hamilton G, Wolfson T, Schroeder ME, Middleton MS, et al. Estimation of Hepatic Proton-Density Fat Fraction by Using MR Imaging at 3.0 T. Radiology. 2011;258:749–759. PubMed PMC

Mashhood A, Railkar R, Yokoo T, Levin Y, Clark L, Fox-Bosetti S, et al. Reproducibility of Hepatic Fat Fraction Measurement by Magnetic Resonance Imaging. J Magn Reson Imaging. 2013;37:1359–1370. PubMed

Mire-Sluis AR, Barrett YC, Devanarayan V, Koren E, Liu H, Maia M, et al. Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J Immunol Methods. 2004;289:1–16. PubMed

Shankar G, Devanarayan V, Amaravadi L, Barrett YC, Bowsher R, Finco-Kent D, et al. Recommendations for the validation of immunoassays used for detection of host antibodies against biotechnology products. J Pharm Biomed Anal. 2008;48:1267–1281. PubMed

Desnick RJ, Schuchman EH. Enzyme replacement and enhancement therapies: lessons from lysosomal disorders. Nature Reviews Genetics. 2002;3:954–966. PubMed

Anderson RA, Bryson GM, Parks JS. Lysosomal acid lipase mutations that determine phenotype in Wolman and cholesterol ester storage disease. Mol Genet Metab. 1999;68:333–345. PubMed

Thelwall PE, Smith FE, Leavitt MC, Canty D, Hu W, Hollingsworth KG, et al. Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance. J Hepatol. 2013;59:543–549. PubMed PMC

Hoeg JM, Demosky SJ, Jr, Pescovitz OH, Brewer HB., Jr Cholesteryl ester storage disease and Wolman disease: phenotypic variants of lysosomal acid cholesteryl ester hydrolase deficiency. Am J Hum Genet. 1984;36:1190–1203. PubMed PMC

Todoroki T, Matsumoto K, Watanabe K, Tashiro Y, Shimizu M, Okuyama T, et al. Accumulated lipids, aberrant fatty acid composition and defective cholesterol ester hydrolase activity in cholesterol ester storage disease. Ann Clin Biochem. 2000;37:187–193. PubMed

Puri P, Mirshahi F, Cheung O, Natarajan R, Maher JW, Kellum JM, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology. 2008;134:568–557. PubMed

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

Clinical Features of Lysosomal Acid Lipase Deficiency

Zobrazit více v PubMed

ClinicalTrials.gov
NCT01757184