Tony Sampson, Mercer University College of Pharmacy
According to an article published in The Journal of Hepatology, lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease that is caused by deleterious mutations in the LIPA gene. It also states that dyslipidemia and progressive liver disease are both characteristic features of LAL-D and patients normally present with elevated transaminase levels, hepatomegaly, and/or microvesicular steatosis. 
Per an article posted to Atherosclerosis, there are no disease-specific treatment available for patients with LAL-D. It goes on to state that existing approaches focus on supportive therapies to reduce the burden of disease complications and that clinical trials are ongoing to investigate the safety and efficacy of sebelipase alfa, a recombinant human lysosomal acid lipase that addresses the underlying defect in patients with LAL-D. 
|Title: A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency |
|Design||Multicenter, randomized, double-blind, phase III, placebo-controlled study; N= 66|
|Objective||To show that sebelipase alfa decreases alanine aminotransferase (ALT) compared to placebo|
|Study Groups||Sebelipase alfa (n= 36) and placebo group (n= 30)|
|Methods||Patients were randomly assigned in a 1:1 ratio to receive an intravenous infusion of sebelipase alfa dose of 1 mg/kg or placebo every other week for 20 weeks before entering the open-label extension period at which point all patients were to receive sebelipase alfa.|
|Primary Outcome Measure||ALT normalization compared with placebo|
|Baseline Characteristics||Characteristic||Sebelipase alfa (n= 36)||Placebo (n= 30)|
|Mean – yr||17 ± 12||15 ± 10|
|Sex — no. (%)|
|Male||18 (50)||15 (50)|
|Female||18 (50)||15 (50)|
|Race – no. (%)†|
|White||27 (75)||28 (93)|
|Other||9 (25)||2 (7)|
|Mean — U/L||105 ± 34||78 ± 35|
|≥ 3x Upper limit of the normal range —no. (%)‡||10 (28)||8 (27)|
|† Race was self reported
‡ The upper limit of the normal range for alanine aminotransferase that was used by the central laboratory was 34 U/L for female patients four to sixty-nine years of age and male patients four to ten years of age and 43 U/L for male patients ten to sixty-nine years of age.
|Results||ALT normalization in the sebelipase alfa group compared to placebo (31% vs. 7%, p= 0.03)|
|Adverse Events||Common Adverse Events: Headache (28%), fever (25%), oropharyngeal pain (17%), nasopharyngitis (11%), asthenia (8%), constipation (8%), nausea (8%)|
|Serious Adverse Events: N/A|
|Percentage that Discontinued due to Adverse Events: N/A|
|Study Author 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.|
Results of this study demonstrated that patients receiving enzyme replacement therapy with sebelipase alfa was superior to placebo in in producing significant reductions in serum aminotransferase levels. One limitation of the study is the predominantly pediatric population precluded assessment of long-term progression of liver disease, cardiovascular events, and mortality. In conclusion, this study demonstrated that sebelipase alfa may have value in reducing the risk of fibrosis of the liver and progression to cirrhosis in patients with LAL-D.
- Bernstein DL, Hülkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013;58(6):1230-43.
- Reiner Ž, Guardamagna O, Nair D, et al. Lysosomal acid lipase deficiency–an under-recognized cause of dyslipidaemia and liver dysfunction. Atherosclerosis. 2014;235(1):21-30.
- Burton BK, Balwani M, Feillet F, et al. A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. N Engl J Med. 2015;373(11):1010-20.