One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency

George A Diaz,Simon A Jones,Maurizio Scarpa,Karl Eugen Mengel,Roberto Giugliani,Nathalie Guffon,Isabela Batsu,Patricia A Fraser,Jing Li,Qi Zhang,Catherine Ortemann-Renon

doi:10.1038/s41436-021-01156-3

Abstract

PurposeTo assess olipudase alfa enzyme replacement therapy for non–central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. MethodsThis phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52. ResultsTwenty patients were enrolled: four adolescents (12–17 years), nine children (6–11 years), and seven infants/early child (1–5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). ConclusionIn this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints.

Highlights

Acid sphingomyelinase deficiency (ASMD) results from pathogenic sequence variants in the SMPD1 (EC3.1.4.12) gene encoding the lysosomal enzyme acid sphingomyelinase (ASM)
ASMD type B is associated with little or no progressive neurological involvement, while ASMD type A/B has neurologic characteristics much less severe than those observed in ASMD type A.3,7
Pediatric patients with chronic forms of ASMD may be at particular risk for early death.[9,10]

Summary

Introduction

Acid sphingomyelinase deficiency (ASMD) (historically Niemann–Pick disease [NPD] types A [OMIM257200], B [OMIM607616], A/B) results from pathogenic sequence variants in the SMPD1 (EC3.1.4.12) gene encoding the lysosomal enzyme acid sphingomyelinase (ASM). While ASM metabolic pathways and consequences of deficient enzyme are complex,[1] sphingomyelin is the primary storage compound. Intracellular sphingomyelin accumulation is especially damaging in lipid-laden macrophages of the reticuloendothelial system, and in the most severe cases in neurons of the central nervous system.[2] Systemic manifestations of ASMD include hepatosplenomegaly, bleeding/bruising, thrombocytopenia, dyslipidemia, interstitial lung disease (ILD), delayed growth and puberty, osteoporosis/osteopenia, liver dysfunction with progressive fibrosis, and cardiac disease.[3,4]. ASMD type B is associated with little or no progressive neurological involvement, while ASMD type A/B has neurologic characteristics much less severe than those observed in ASMD type A.3,7. Pediatric patients with chronic forms of ASMD may be at particular risk for early death.[9,10]

Methods

Results

Conclusion