Enzyme replacement therapy shows promise for rare lysosomal storage disease: The ARISE study

1. Sebelipase alfa treatment significantly improved liver function tests among 31% of patients with lysosomal acid lipase deficiency receiving the drug compared to 7% of patients receiving placebo.

2. A predominantly pediatric outcome limits the generalizability of the study.

Evidence Rating Level: 2 (Good)

Study Rundown: In lysosomal acid lipase deficiency there is a defect in the fat and cholesterol metabolism pathway which leads to accumulation of byproducts in the liver. This autosomal recessive disease can lead to liver damage and cirrhosis. Since it is caused by the absence of a particular enzyme, it is hypothesized that replacing the missing enzyme will help treat the disease.

In this trial, 36 out of the 66 patients with lysosomal acid lipase deficiency were treated with sebelipase alfa, a molecule designed to replace the missing lysosomal acid lipase enzyme intravenously every 2 weeks. The remaining were the placebo group. A significantly larger proportion of the patients treated with sebelipase alfa had normalization of their liver function tests compared to those who received placebo. There were also significant improvements in a number of secondary outcomes, indicating that the treatment also helped to correct other aspects of fat and cholesterol metabolism which are affected by the disease.

These results demonstrate that enzyme replacement is associated with improving many of the liver enzyme changes seen in lysosomal acid lipase deficiency. However, definitive data on outcomes such as progression to cirrhosis are still needed from longer-term follow-up studies.

Click to read the study published today, in NEJM

Relevant Reading: Sebelipase alfa over 52 weeks reduces serum transaminases, liver volume and improves serum lipids in patients with lysosomal acid lipase deficiency

In-Depth [randomized controlled trial]: This was a multicenter, randomized, double-blind, placebo-controlled study which included sixty-six patients. The participants were randomized to either the sebelipase alfa or the placebo group for 20 weeks. Subsequently, all patients received the drug in the open-label period.

Patients had to be at least 4 years old, with the diagnosis confirmed by enzyme-activity assays and an ALT level at least 1.5 times the upper limit of normal. Patients who had undergone liver transplants or who had severe liver dysfunction (Child-Pugh C) were excluded. The primary endpoint was normalization of the ALT level. Over a third of the participants were less than 12 years of age. There was an equal proportion of males and females. Most patients were Caucasian. At baseline, all patients had fibrosis, and about a third already had cirrhosis.

Sebelipase alfa treatment was associated with a greater rate of normalization of the ALT than placebo during the double-blind period (31% vs. 7%, p=0.03; mean reduction from baseline: -58 U/L vs. -7 U/L, p<0.001). The decrease from baseline in the mean ALT level was significantly greater in the sebelipase alfa group than the placebo group. Similar results were seen in AST levels (42% vs 3%, p<0.001; mean reduction, -42U/L vs. -6U/L; p<0.001). Other secondary end points which improved with sebelipase alfa treatment included: a decrease in LDL (-28.4% vs. 62.%, p<0.001), a decrease in triglycerides (-25.5% vs.-11.1%, p=0.04), an increase in HDL (19.6% vs. -0.3%, p<0.001) and a decrease in hepatic fat content (-32.0% vs. -4.2%, p<0.001).

The most common adverse events were headache (28%) and fever (19%), though there was no significant difference in the frequency of any of these adverse events between the treatment and placebo groups. As a recombinant human enzyme, sebelipase alfa did lead to anti-drug antibodies in 5 of 35 patients, but these antibodies did not affect either safety or efficacy of the drug.

Image: PD

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