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

AbstractBACKGROUND:
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.).
AuthorsBarbara K Burton, Manisha Balwani, François Feillet, Ivo Barić, T Andrew Burrow, Carmen Camarena Grande, Mahmut Coker, Alejandra Consuelo-Sánchez, 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 Nightingale, 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
JournalThe New England journal of medicine (N Engl J Med) Vol. 373 Issue 11 Pg. 1010-20 (Sep 10 2015) ISSN: 1533-4406 [Electronic] United States
PMID26352813 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Cholesterol, HDL
  • Cholesterol, LDL
  • Alanine Transaminase
  • Sterol Esterase
Topics
  • Adolescent
  • Adult
  • Aged
  • Alanine Transaminase (blood)
  • Biopsy
  • Child
  • Child, Preschool
  • Cholesterol, HDL (blood)
  • Cholesterol, LDL (blood)
  • Double-Blind Method
  • Dyslipidemias (drug therapy, genetics)
  • Female
  • Humans
  • Liver (drug effects, pathology)
  • Male
  • Middle Aged
  • Sterol Esterase (adverse effects, pharmacology, therapeutic use)
  • Wolman Disease (blood, drug therapy)
  • Young Adult

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