Neil Osterweil

November 18, 2014

BOSTON — Enzyme replacement therapy with sebelipase alfa can significantly reduce liver injury, liver fat, and dyslipidemia in patients with lysosomal acid lipase (LAL) deficiency, results from a phase 3 randomized controlled trial show.

"Consistent with other enzyme replacement therapies, sebelipase alfa addresses the root cause of the disease by replacing the deficient enzyme," said Manisha Balwani, MD, from the Icahn School of Medicine at Mount Sinai Medical Center in New York City.

In the ARISE trial, also known as the Acid Lipase Replacement Investigating Safety and Efficacy study, liver function measures, lipid profiles, liver fat content, and liver volume improved significantly in children and adults with LAL deficiency who were treated with the replacement enzyme, Dr. Balwani reported here at The Liver Meeting 2014.

The deficiency, formerly known as cholesteryl ester storage disease, is a genetic disorder caused by an enzyme shortage that has two inter-related effects: progressive accumulation of cholesterol esters and triglycerides in cells and tissues, and disruption of lipid metabolism.

The cholesterol esters and triglycerides are stored primarily in the liver, and lead to liver injury, marked by persistently elevated transaminase levels, hepatomegaly, elevated low-density lipoprotein (LDL) and reduced HDL high-density lipoprotein (HDL) cholesterol levels, cirrhosis, and early-onset cardiovascular disease.

In an earlier phase 1/2 study (NCT01307098), sebelipase alfa, a recombinant human replacement enzyme, reduced liver transaminase levels, improved lipid profiles, and reduced the fraction of fat in the livers of adults with the deficiency.

Dr. Balwani's team involved investigators from Asia, Australia, Europe, and North and South America.

Patients who were 4 years and older and who had alanine aminotransferase levels at least 1.5 times the upper limit of normal were eligible for the study.

In the double-blind phase of the study, 36 patients received sebelipase alfa infusions 1 mg/kg once every other week for 20 weeks, and 30 patients received placebo.

Median patient age was 13.5 years (range, 4 - 55) in the enzyme replacement group and 13 years (range, 4 - 58 years) in the placebo group. Mean transaminase and lipid levels were well balanced between the groups.

At the end of the 20-week treatment period, outcomes were significantly better in the enzyme group than in the placebo group for seven of nine measures.

Table. ARISE Outcomes After 20-Week Treatment Period

End Point Sebelipase Alfa Group, % Placebo Group, % P Value
   Alanine aminotransferase 31.0 7.0 0.027
   Aspartate aminotransferase 42.0 3.0 <.001
Change from baseline      
   LDL cholesterol –28.0 –6.0 <.001
   HDL cholesterol 20.0 –0.3 <.001
   Non-HDL cholesterol –28.0 –7.0 <.001
   Triglyceride –25.0 –11.0 .038
   Liver fat content –32.0 –4.0 <.001
   Steatosis 63.0 40.0 ns
   Liver volume –10.3 –2.7 ns


There were 31 adverse events in the enzyme group and 28 in the placebo group. Most were mild and not related to sebelipase alfa therapy. There were two serious adverse events: an atypical infusion-related reaction, and a case of gastritis judged to be unrelated to therapy.

In the enzyme group, 5.7% of patients had antidrug antibodies at more than one timepoint during the study, but there were no apparent effects on safety or efficacy.

After the 20-week double-blind phase of the study, 65 of the 66 patients continued in an open-label phase. Safety during the open-label period was similar to that seen during the double-blind phase, Dr. Balwani reported.

"It's really impressive to see the improvements in biochemistry, as well as the lipids, and in reduction in hepatic fat," session comoderator Keith Lindor, MD, from the College of Health Solutions at Arizona State University in Tempe, said in an interview with Medscape Medical News.

This study was supported by Synageva BioPharma Corp. Dr. Balwani and Dr. Lindor have disclosed no relevant financial relationships.

The Liver Meeting 2014: American Association for the Study of Liver Diseases (AASLD). Abstract LB-5. Presented November 10, 2014.


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