Efficacy and safety of sebelipase alfa in children and adults with Lysosomal Acid Lipase Deficiency: results of a phase 3 trial

Abstract

Lysosomal Acid Lipase (LAL) Deficiency is a progressive multisystem disease that is an underappreciated cause of cirrhosis, severe dyslipidemia and early onset atherosclerosis. A phase 3, double-blind, placebo-controlled trial (NCT01757184) randomized affected children and adults (N=66) to placebo or sebelipase alfa 1 mg/kg every other week for 20 weeks. Primary endpoint was ALT normalization. Secondary endpoints included additional important efficacy assessments, safety and immunogenicity. Medically important abnormalities were common at baseline including fibrosis and cirrhosis in 100% and 31% respectively of biopsied patients (n=32) and a median LDL of 204.0mg/dL (range 70-378mg/dl). After 20 weeks, ALT normalization (ULN range 34-43 U/L) was achieved in 31% of the sebelipase alfa group and 7% of the placebo group. Multiple secondary efficacy endpoints were also met including relative reduction in LDL-C, non-HDL-c, and triglycerides and relative increase in HDL-C. Over 350 infusions of sebelipase alfa were given during the double-blind period. The number of patients with AEs was similar in each arm. During the double-blind period, most AEs were mild and unrelated to sebelipase alfa; 6 patients experienced infusion-associated reactions (4 placebo; 2 sebelipase alfa). Dosing was paused in 1 patient after an atypical infusion-related reaction following sebelipase alfa treatment. Sebelipase alfa for 20 weeks demonstrated statistically significant improvements in ALT normalization and in a number of other important disease related abnormalities including marked reductions in LDL. The safety profile appears favorable and infusions were generally well tolerated.