Sebelipase alfa 20mg/10ml solution for infusion vials

BACKGROUND: Infants presenting with lysosomal acid lipase deficiency have marked failure to thrive, diarrhea, massive hepatosplenomegaly, anemia, rapidly progressive liver disease, and death typically in the first 6 months of life; the only available potential treatment has been hematopoietic stem cell transplantation, which is associated with high morbidity and mortality in this population. The study objective was to evaluate safety and efficacy (including survival) of enzyme replacement with sebelipase alfa in infants with lysosomal acid lipase deficiency. This is an ongoing multicenter, open-label, phase 2/3 study conducted in nine countries. The study enrolled infants with growth failure prior to 6 months of age with rapidly progressive lysosomal acid lipase deficiency; they received once-weekly doses of sebelipase alfa initiated at 0.35 mg/kg with intrapatient dose escalation up to 5 mg/kg. The main outcome of interest is survival to 12 months and survival beyond 24 months of age. RESULTS: Nine patients were enrolled; median age at baseline was 3.0 months (range 1.1-5.8 months). Sixty-seven percent (exact 95% CI 30%-93%) of sebelipase alfa-treated infants survived to 12 months of age compared with 0% (exact 95% CI 0%-16%) for a historical control group (n = 21). Patients who survived to age 12 months exhibited improvements in weight-for-age, reductions in markers of liver dysfunction and hepatosplenomegaly, and improvements in anemia and gastrointestinal symptoms. Three deaths occurred early (first few months of life), two patients died because of advanced disease, and a third patient died following complications of non-protocol-specified abdominal paracentesis. A fourth death occurred at 15 months of age and was related to other clinical conditions. The five surviving patients have survived to age ≥24 months with continued sebelipase alfa treatment; all have displayed marked improvement in growth parameters and liver function. Serious adverse events considered related to sebelipase alfa were reported in one of the nine infants (infusion reaction: tachycardia, pallor, chills, and pyrexia). Most infusion-associated reactions were mild and non-serious. CONCLUSION: Sebelipase alfa markedly improved survival with substantial clinically meaningful improvements in growth and other key disease manifestations in infants with rapidly progressive lysosomal acid lipase deficiency TRIAL REGISTRATION: Clinicaltrials.gov NCT01371825 . Registered 9 June 2011.

Abstract licence: CC BY

BACKGROUND AND AIMS: In patients with lysosomal acid lipase deficiency (LAL-D), elevations in alanine and aspartate aminotransferases (ALT, AST) are associated with liver damage. The objective of this analysis was to evaluate aminotransferase levels in patients treated with sebelipase alfa enzyme replacement therapy and untreated patients. METHODS: Patients in this observational study were from the International LAL-D Registry and included untreated and treated patients who started sebelipase alfa at age ≥ 6 months. Patients in the longitudinal analysis must have had baseline and longitudinal measures of ALT or AST. A subanalysis was performed on data from patients with 3 consecutive annual follow-up measures. RESULTS: Of 186 patients included in this analysis, 125 were treated with sebelipase alfa. Median age at diagnosis was 9.1 y for treated patients and 20.6 y for untreated patients. Baseline ALT levels were above the upper limit of normal in 93% of children aged < 18 years and 68% of adults aged ≥ 18 years. Among 53 treated patients who had ALT results reported at 3 consecutive annual measurements, 22 (42%) had ALT levels within normal limits after 1 year of sebelipase alfa treatment. Results were similar for AST. A repeated measures regression model of data from treated patients showed significant reductions from baseline in both ALT and AST levels across 3 years of the study. Untreated patients had no appreciable changes in aminotransferase elevations over time. CONCLUSIONS: Aminotransferase levels were elevated in most patients with LAL-D at baseline. There were sustained improvements with sebelipase alfa treatment. TRIAL REGISTRATION: International LAL-D Registry: NCT01633489, EUPAS13276.

Abstract licence: CC BY