• Liver Conditions
• Lipid Disorders Hepatology Clinical Trials
• Deficiency Disorders

• Liver Conditions
• Lipid Disorders
• Hepatology
• Hepatology Clinical Trials
• Deficiency Disorders

Lysosomal acid lipase deficiency (LAL-D) is an autosomal genetic recessive disorder that leads to an inability to break down lipid particles in the lysosome, and it is associated with early-onset cirrhosis and cardiovascular disease. Enzyme replacement therapy has been transformational for patients with LAL-D. Sebelipase alfa is a recombinant form of the human lysosomal acid lipase (LAL) enzyme used to replace the deficient enzyme in LAL-D.

The Acid Lipase Replacement Investigating Safety and Efficacy trial [ARISE; NCT01757184] was a randomized, double-blind, placebo-controlled phase 3 study designed to evaluate sebelipase alfa in 66 patients with LAL-D. Patients were randomized to receive 1 mg/kg sebelipase alfa or placebo every other week for 20 weeks during the double-blind phase, after which all patients continued on the study drug. LAL-D patients aged ≥ 4 years with an elevated alanine transaminase (ALT) level (≥ 1.5 × the upper limit of normal) were enrolled and permitted to continue on stable doses of background lipid-lowering medications. Patients with a history of liver or hematopoietic stem cell transplant were excluded, as were those with Child-Pugh C status. The primary study end point was liver injury as measured by normalization of ALT. Other end points included the effect on lipid metabolism, as well as a reduction in liver volume and fat content.

Participants had a median age of 13 years, with the majority being younger than 18 years. As expected, the baseline serum transaminases in this group were elevated. Mean gamma-glutamyl transferase (GGT) was normal, whereas low-density lipoprotein (LDL) levels were very high (mean, 190 to 230 mg/dL). Baseline liver biopsy was available for 32 participants (mean age, 12 years). All of these patients had fibrosis; 47% had bridging fibrosis, and 31% cirrhosis. Dyslipidemia was present in 58% (38/66) of patients, including the 24% who were taking lipid-lowering medications.

Hierarchical fixed sequence testing was used to test across the secondary end points. In this method, if one of the secondary end points did not achieve significance, the subsequent end points were nullified. Treatment with sebelipase alfa was associated with ALT normalization in significantly more patients compared with placebo (31% vs 7%; P = .027). Patients treated with sebelipase alfa had a mean reduction in ALT units/L of 58 (53%) compared with 7 (6%) for placebo-treated patients (P < .001). Significant effects were also seen for 6 of the secondary end points (Table 1).

The reduction in ALT was accompanied by a reduction in liver fat content of 32% for patients treated with sebelipase alfa versus 4% for placebo-treated patients (P < .001). Other liver assessments are shown in Table 2.

Patients treated with sebelipase alfa also realized significant reductions in LDL (−28%) and increases in HDL (+20%) compared with placebo-treated patients (−6% and −0.3% LDL and HDL, respectively; both P < .001).

Most adverse events were mild and not related to the study drug. There were 2 serious adverse events in the sebelipase alfa group (an atypical infusion reaction and gastritis).

ALT levels normalized in placebo-treated patients after they were switched to sebelipase alfa. Patients treated with sebelipase alfa had a sustained response and improvement in ALT up to week 36.

Consistent with other forms of enzyme replacement therapy, sebelipase alfa addresses the cause of LAL-D by replacing the deficient enzyme.

• © 2014 MD Conference Express®