Survival, growth, and safety findings in patients with rapidly progressive, infantile-onset LAL-D: Results from the international LAL-D registry

In symptomatic infants, lysosomal acid lipase deficiency (LAL-D; historically Wolman disease) is characterized by a rapidly progressive disease course of hepatosplenomegaly and liver disease. This course includes liver failure, malabsorption and growth failure, and systemic inflammation, such as hemophagocytic lymphohistiocytosis, typically leading to death by 6 months of age if untreated. Sebelipase alfa (KANUMA®; Alexion, AstraZeneca Rare Disease, Boston, MA) is a recombinant human LAL (a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme) approved for the treatment of LAL-D in infants with rapidly progressive disease as well as in children and adults with LAL-D. Previous studies showed that enzyme replacement therapy (ERT) with sebelipase alfa led to survival with improved growth and development, hematologic parameters, and liver parameters and was well tolerated. We report long-term outcomes in 29 patients with rapidly progressive LAL-D who were symptomatic in infancy using patient data from the International LAL-D Registry, an ongoing observational, multicenter, international registry (NCT01633489) that collects data on patients with LAL-D. Among these 29 patients treated with sebelipase alfa, 41 % were male, and 28 % had participated in clinical trials with sebelipase alfa. Median age (Q1, Q3) was 2.3 months (1.8, 3.1) at the start of ERT. Patients received a starting ERT dose of ≤1 mg/kg or ≥3 mg/kg per week. In patients who had participated in clinical trials of sebelipase alfa, the starting dose was driven by the clinical trial protocol and was between 0.2 and 1.0 mg/kg per week. Overall, 27 of 29 (93 %) patients survived during the median observation time (Q1, Q3) of 6.2 years (3.5, 8.4). At baseline, 11 patients had abnormally low weight-for-age z scores (<-2); for 5 of these patients, weight stabilized after 6 to 12 months of treatment (z scores between -2 and 2). Adverse events occurred in 23 (79 %) patients. Eleven (38 %) patients experienced adverse events potentially related to sebelipase alfa, which were generally not severe and most resolved. Four patients among 7 tested developed antidrug antibodies, and 3 had positive results for neutralizing antidrug antibodies. These results confirmed the dramatic survival and metabolic benefit associated with sebelipase alfa ERT in patients with symptomatic, rapidly progressive LAL-D.