Survival in infants treated with sebelipase Alfa for lysosomal acid lipase deficiency: an open-label, multicenter, dose-escalation study

Abstract

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.

Keywords: Hemophagocytic lymphohistiocytosis; Lysosomal acid lipase deficiency; Sebelipase alfa; Survival; Wolman disease.

Figures

Fig. 1

Patient flow and disposition. Two patients died during screening; three patients died after enrollment, all of whom received four or fewer doses of sebelipase alfa

Fig. 2

Survival from birth to 12 months of age. Kaplan-Meier analyses of (a) historical control group of untreated patients with early growth failure (n = 21) from natural history study of infants with LAL deficiency (LAL-1-NH01; data on file, Alexion Pharmaceuticals, Inc.) [7] and (b) the primary efficacy set of the present phase 2/3 study (N = 9). Patients in the historical control group were considered untreated if they had not received hematopoietic stem cell transplant, liver transplant, or enzyme replacement therapy. Growth failure was defined by 1) decreased body weight across ≥2 of the 11 major centiles on a standard WHO weight-for-age chart, or 2) body weight in kilograms below the 10th centile on a standard WHO weight-for-age chart and no weight gain for the previous 2 weeks, or 3) loss of ≥5% of birth weight in children who are >2 weeks of age

Fig. 3

Individual growth curves over time for the 6 patients who met the primary endpoint (12-month survival). ADA = time at anti-drug antibody detection. *Due to the window of time associated with scheduled assessments, no weight was collected at 12 months for patient 05–001; therefore, the next available weight data point was used to graph the weight at 12 months; this patient died at age 15 months

Fig. 4

Changes in serum transaminases. Individual patient results for transaminases over time: (a) alanine aminotransferase (ALT) and (b) aspartate aminotransferase (AST). EBV = Epstein-Barr virus; qow = every-other-week dosing. To convert to SI units (μkat/L), multiply by 0.0167