Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency

Mol Genet Metab. Sep-Oct 2015;116(1-2):88-97. doi: 10.1016/j.ymgme.2015.05.013. Epub 2015 May 30.


Background: Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy.

Methods: Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks.

Results: All patients successfully reached 3.0mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed.

Conclusions: This study provides proof-of-concept for the safety and efficacy of within-patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD.

Trial registration: NCT01722526.

Keywords: Dose escalation; Niemann–Pick disease type B; Nonneuronopathic ASMD; Olipudase alfa; Recombinant human acid sphingomyelinase.

Publication types

  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Replacement Therapy
  • Female
  • Humans
  • Lipids / blood
  • Liver / drug effects
  • Liver / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Male
  • Middle Aged
  • Niemann-Pick Disease, Type A / drug therapy*
  • Recombinant Proteins / administration & dosage*
  • Recombinant Proteins / adverse effects
  • Recombinant Proteins / therapeutic use
  • Sphingomyelin Phosphodiesterase / administration & dosage
  • Sphingomyelin Phosphodiesterase / adverse effects
  • Sphingomyelin Phosphodiesterase / therapeutic use*
  • Sphingomyelins / pharmacokinetics
  • Young Adult


  • Biomarkers
  • Lipids
  • Recombinant Proteins
  • Sphingomyelins
  • Sphingomyelin Phosphodiesterase
  • olipudase alfa

Associated data