Long‐Term Safety and Clinical Outcomes With Olipudase Alfa Enzyme Replacement Therapy in Children and Adolescents With Acid Sphingomyelinase Deficiency

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disease characterized by hepatosplenomegaly, pulmonary dysfunction, dyslipidemia, and growth deficits. Olipudase alfa (recombinant-human ASM) is the only treatment for non-central-nervous-system ASMD manifestations in children and adults. An open-label long-term study followed 4 to 8 years of olipudase alfa treatment in 20 children and adolescents with ASMD (baseline age (years) 1.5-17.5). At final assessments, splenomegaly and hepatomegaly were reduced relative to baseline (mean percent decrease in spleen and liver volumes 78% ± 1.2% and 59.8% ± 1.5%, respectively). Baseline splenomegaly was severe (spleen volume > 15 MN [multiples of normal]) or moderate (5-15 MN) (n = 12 and n = 8, respectively) versus mild/absent (< 5 MN) (n = 12) or moderate (n = 8) at final assessment. Baseline hepatomegaly was severe (liver volume > 2.5 MN) (n = 10) or moderate (1.25-2.5 MN) (n = 10) versus mild/absent (< 1.25 MN) (n = 19) or moderate (n = 1) at final assessment. Among nine individuals able to perform assessments, diffusing capacity of the lung for carbon monoxide (DL_CO) impairment was severe (< 40%) (n = 1), moderate (40%-60%) (n = 4), or mild (60%-80%) (n = 4) at baseline versus absent (n = 4), mild (n = 4) or moderate (n = 1) at final assessment. Mean percent increase in DL_CO was 53.7% ± 6.5%. At baseline, 10/20 children had clinical short stature (height Z-scores ≤ - 2) at baseline versus 0/20 at the final assessment. Atherogenic lipid profiles and liver function tests normalized within 2 years and remained stable. Adverse events were mostly mild or moderate, with 4 individuals experiencing 7 serious adverse events, all recovered/resolved. Interpretation: Enzyme replacement therapy with olipudase alfa in children and adolescents with chronic ASMD was well-tolerated with clinically meaningful improvements in multiple disease parameters. Trial Registration: NCT02004704.