Rare Disease Report

Enzyme Replacement Therapy in Patients with Lysosomal Acid Lipase Deficiency

DECEMBER 30, 2014
Christin Melton

On the heels of positive findings from a randomized, double-blind, phase III trial comparing sebelipase alfa (SBC-102) with placebo in individuals with lysosomal acid lipase (LAL) deficiency, Synageva BioPharma submitted a Biologics License Application (BLA) to the US Food and Drug Administration (FDA) in December 2014 with a request for priority review. The FDA has already given the drug a Breakthrough Therapy designation for infants with LAL deficiency. Investigators presented data from the phase III trial (NCT01757184) at the 65th Annual Meeting of the American Association for the Study of Liver Diseases held in Boston, Massachusetts, from November 7-11, 2014, which showed that sebelipase alfa improved several hallmarks of LAL deficiency and was well tolerated.

Baseline Characteristics

In the study, 66 adults and children aged 4 to 58 years (median age, 13 years) with LAL deficiency were randomly assigned to receive infusions of sebelipase alfa 1 mg/kg or placebo every other week for 20 weeks.1 At study entry, all patients had an alanine aminotransferase (ALT) level 1.5 times the upper limit of normal. Most patients had dyslipidemia at study entry (median level of low-density lipoprotein cholesterol [LDL-C], 204 mg/dL), and 39% were taking cholesterol-reducing medications. For the 32 patients who underwent a liver biopsy at baseline, results showed 47% had bridging fibrosis and 31% had cirrhosis.

Efficacy Outcomes

Significantly more patients in the sebelipase alfa arm than the placebo arm achieved a normalized ALT level by the end of the study (31% vs 7%, respectively; P =.027), which was the trial's primary endpoint. The mean decrease in ALT with sebelipase alfa was 57.9 U/L versus 6.7 U/L with placebo. Relative to placebo, sebelipase alfa was also associated with significant reductions in levels of LDL-C, triglycerides, and hepatic fat fraction (Table). Patients taking sebelipase alfa were also significantly more likely than patients taking placebo to experience an increase in the level of high-density lipoprotein cholesterol and normalization of aspartate aminotransferase levels.

Table. Efficacy Outcomes at 20 Weeks

  Sebelipase alfa
Arm (n = 36)
Arm (n = 30)
P Value
 Patients with normalized ALT 31 7 .027
 Patients with normalized AST 42 3 <.001
 Change in LDL-C -28 -6 <.001
 Change in triglycerides -25 -11 .038
 Change in HDL-C 20 -.3 <.001
 Change in hepatic fat fraction by MRI -32 -4 <.001
 Patients with improvement in steatosis 63 40 NS
 Change in liver volume -10.3 -2.7 NS
ALT = alanine aminotransferase; AST = aspartate aminotransferase; HDL = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; MRI = magnetic resonance imaging.

Safety Outcomes

Most adverse events were mild. Patients treated with sebelipase alfa were slightly more likely than patients taking placebo to experience headaches, pyrexia, oropharyngeal pain, nasopharyngitis, gastrointestinal events, and fatigue. One patient in the sebelipase alfa arm had a severe atypical reaction to the infusion, which was the only serious treatment-related adverse event that occurred during the study. Although that patient discontinued the study, the remaining 65 patients enrolled in an open-label extension study evaluating long-term use of sebelipase alfa. Preliminary data from the extension study showed that outcomes for patients who crossed over from placebo to sebelipase alfa were similar to those observed in the previous study’s sebelipase alfa arm.

About LAL Deficiency

LAL deficiency is a rare lysosomal disorder that occurs when someone inherits 2 mutations of the gene responsible for producing the LAL enzyme. The body requires LAL to break down cholesteryl esters and triglycerides. In patients with LAL deficiency, these lipids begin to accumulate primarily in the liver, spleen, and macrophages but may also affect other organs. The disorder is a common cause of hepatic steatosis and should be considered in the differential diagnosis for nonalcoholic fatty liver disease.
Infants with LAL deficiency rarely survive past 6 months. Adults and children who have the more common late-onset LAL deficiency often develop cardiovascular complications in addition to progressive liver disease, and have a significantly shorter life expectancy. If approved, sebelipase alfa would be the first enzyme replacement therapy available for patients with LAL deficiency.


1.         Yang Y, Eckert S, Rojas-Cario S, et al. Safety of sebelipase alfa as an enzyme replacement therapy in children and adults with lysosomal acid lipase deficiency. Presented at: the 65th Annual Meeting of the American Association for the Study of Liver Diseases; November 7-11, 2014; Boston, MA. Abstract LB-5. http://aasld.multieposter.com/2014/LB-5.pdf

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