Phase 3 Study Shows Sebelipase Alfa to be Safe and Effective for LAL Deficiency

Lorraine L. Janeczko, MPH

Patients with lysosomal acid lipase (LAL) deficiency treated with sebelipase alfa (SA) infusions for 20 weeks showed significant improvements in alanine aminotransferase (ALT) normalization and in a number of other important disease-related abnormalities, including marked drops in low-density lipoprotein cholesterol (LDL-C) and improvements in other lipid parameters, in a recent study.
SA was generally well tolerated, the safety profile appeared favorable, and the efficacy continued during open-label treatment, according to results presented in a poster at the National Lipid Association Scientific Sessions, June 11-14, 2015, in Chicago, Illinois.1
LAL, an enzyme coded by the LIPA gene, controls cholesterol ester (CE) and triglyceride hydrolysis. LAL deficiency is a progressive multisystem disease caused by mutations that lead to typically massive systemic accumulation of CEs and triglycerides in the lysosomes of various tissues. With LAL, CEs build up throughout organs including the liver, spleen, gastrointestinal tract, and blood vessel walls, causing progressive organ damage. The disorder is an insufficiently recognized cause of cirrhosis, severe dyslipidemia, and early-onset atherosclerosis.1,2
SA is the first enzyme replacement therapy for patients with LAL deficiency, who currently have no other effective treatments available.
To examine the safety and efficacy of SA, lead study author Sandra Rojas-Caro, MD, and colleagues from Synageva BioPharma Corp in Lexington, Massachusetts, conducted a phase 3, double-blind, placebo-controlled trial that randomized 66 children and adults with LAL to 1 mg/kg every other week of SA or placebo, for 20 weeks. At 20 weeks, the open-label period began and all study participants received SA.
The study’s primary endpoint was ALT normalization, and its secondary endpoints included lipid level changes, other efficacy assessments, safety, and immunogenicity.
The researchers found abnormalities to be common at baseline, including median LDL-C of 204.0 mg/dL (range, 70 mg/dL-378 mg/dL). LDL-C was 190 mg/dL or higher in 38 patients (58%), including 9 of 38 (24%) who were on lipid-lowering medications. Liver abnormalities included fibrosis (100%), bridging fibrosis with an Ishak score of 3 or 4 (47%), and cirrhosis (31%) in biopsied patients.
After 20 weeks of treatment, 31% of participants in the SA group and 7% in the placebo group achieved ALT normalization, considered to be the upper-limit-of-normal range (34 U/L-43 U/L; P = .0271).
Secondary efficacy endpoints met by the participants included the relative reduction in LDL-C (-22.2%; P <.0001), non–high-density lipoprotein cholesterol (HDL-C; -21.0%; P <.0001), and triglycerides (-14.3%; P = .0375), and the relative increase in HDL-C (+19.9%; P <.0001) compared with placebo.
During the open-label phase of the study, participants in the SA group continued to improve. In patients transitioned from placebo to SA, treatment effects were consistent with those seen in the SA-treated patients during the double-blind period.
The safety profiles in the double-blind and open-label periods were consistent. Over 350 SA infusions were given during the double-blind period, and the number of patients with adverse events (AEs) in both groups was similar. Most AEs were mild and unrelated to the drug: 6 patients experienced infusion-associated reactions (2 SA vs 4 placebo). In one patient, SA dosing was paused after an atypical infusion-related reaction.


1. Rojas-Caro S, Burton B, Valayannopoulos V, et al. Efficacy and safety of sebelipase alfa in children and adults with lysosomal acid lipase deficiency: results of a phase 3 trial. Presented at: the National Lipid Association Scientific Sessions 2015; June 11-14, 2015; Chicago, IL. Abstract 123.

2. Lysosomal acid lipase deficiency (LAL D) is a disease of massive, systemic lysosomal lipid accumulation. Accessed June 13, 2015.

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