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 M Laukaitis, Eugen Mengel, Edward G. Neilan, Scott Nightingale & 11 others Heidi 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 journalArticle

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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

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

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Enzyme Replacement Therapy
Placebos
Alanine Transaminase
Fibrosis
Sterol Esterase
Lipids
Patient Safety
Dyslipidemias
Random Allocation
Endocytosis
Lipid Metabolism
LDL Cholesterol
Body Weight
Sebelipase alfa
Lysosomal acid lipase deficiency
Biopsy
Safety
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Burton, B. K., Balwani, M., Feillet, F., Baric, I., Burrow, T. A., Grande, C. C., ... Quinn, A. G. (2015). A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. New England Journal of Medicine, 373(11), 1010-1020. https://doi.org/10.1056/NEJMoa1501365

A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. / Burton, Barbara K.; Balwani, Manisha; Feillet, Francois; Baric, Ivo; Burrow, T. Andrew; Grande, Carmen Camarena; Coker, Mahmut; Consuelo-Sanchez, Alejandra; Deegan, Patrick; Di Rocco, Maja; Enns, Gregory M.; Erbe, Richard; Ezgu, Fatih; Ficicioglu, Can; Furuya, Katryn N.; Kane, John; Laukaitis, Christina M; Mengel, Eugen; Neilan, Edward G.; Nightingale, Scott; Peters, Heidi; Scarpa, Maurizio; Schwab, K. Otfried; Smolka, Vratislav; Valayannopoulos, Vassili; Wood, Marnie; Goodman, Zachary; Yang, Yijun; Eckert, Stephen; Rojas-Caro, Sandra; Quinn, Anthony G.

In: New England Journal of Medicine, Vol. 373, No. 11, 10.09.2015, p. 1010-1020.

Research output: Contribution to journalArticle

Burton, BK, Balwani, M, Feillet, F, Baric, I, Burrow, TA, Grande, CC, Coker, M, Consuelo-Sanchez, A, Deegan, P, Di Rocco, M, Enns, GM, Erbe, R, Ezgu, F, Ficicioglu, C, Furuya, KN, Kane, J, Laukaitis, CM, Mengel, E, Neilan, EG, Nightingale, S, Peters, H, Scarpa, M, Schwab, KO, Smolka, V, Valayannopoulos, V, Wood, M, Goodman, Z, Yang, Y, Eckert, S, Rojas-Caro, S & Quinn, AG 2015, 'A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency', New England Journal of Medicine, vol. 373, no. 11, pp. 1010-1020. https://doi.org/10.1056/NEJMoa1501365
Burton BK, Balwani M, Feillet F, Baric I, Burrow TA, Grande CC et al. A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. New England Journal of Medicine. 2015 Sep 10;373(11):1010-1020. https://doi.org/10.1056/NEJMoa1501365
Burton, Barbara K. ; Balwani, Manisha ; Feillet, Francois ; Baric, Ivo ; Burrow, T. Andrew ; Grande, Carmen Camarena ; Coker, Mahmut ; Consuelo-Sanchez, Alejandra ; Deegan, Patrick ; Di Rocco, Maja ; Enns, Gregory M. ; Erbe, Richard ; Ezgu, Fatih ; Ficicioglu, Can ; Furuya, Katryn N. ; Kane, John ; Laukaitis, Christina M ; Mengel, Eugen ; Neilan, Edward G. ; Nightingale, Scott ; Peters, Heidi ; Scarpa, Maurizio ; Schwab, K. Otfried ; Smolka, Vratislav ; Valayannopoulos, Vassili ; Wood, Marnie ; Goodman, Zachary ; Yang, Yijun ; Eckert, Stephen ; Rojas-Caro, Sandra ; Quinn, Anthony G. / A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency. In: New England Journal of Medicine. 2015 ; Vol. 373, No. 11. pp. 1010-1020.
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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",
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T1 - A phase 3 trial of sebelipase alfa in lysosomal acid lipase deficiency

AU - Burton, Barbara K.

AU - Balwani, Manisha

AU - Feillet, Francois

AU - Baric, Ivo

AU - Burrow, T. Andrew

AU - Grande, Carmen Camarena

AU - Coker, Mahmut

AU - Consuelo-Sanchez, Alejandra

AU - Deegan, Patrick

AU - Di Rocco, Maja

AU - Enns, Gregory M.

AU - Erbe, Richard

AU - Ezgu, Fatih

AU - Ficicioglu, Can

AU - Furuya, Katryn N.

AU - Kane, John

AU - Laukaitis, Christina M

AU - Mengel, Eugen

AU - Neilan, Edward G.

AU - Nightingale, Scott

AU - Peters, Heidi

AU - Scarpa, Maurizio

AU - Schwab, K. Otfried

AU - Smolka, Vratislav

AU - Valayannopoulos, Vassili

AU - Wood, Marnie

AU - Goodman, Zachary

AU - Yang, Yijun

AU - Eckert, Stephen

AU - Rojas-Caro, Sandra

AU - Quinn, Anthony G.

PY - 2015/9/10

Y1 - 2015/9/10

N2 - 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

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