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

Melissa P. Wasserstein, Simon A. Jones, Handrean Soran, George A. Diaz, Natalie Lippa, Beth L. Thurberg, Kerry Culm-Merdek, Elias Shamiyeh, Haig Inguilizian, Gerald F. Cox, Ana Cristina Puga

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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 3.0. mg/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 23.4. h 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.

Original languageEnglish (US)
Pages (from-to)88-97
Number of pages10
JournalMolecular Genetics and Metabolism
Issue number1-2
StatePublished - Sep 1 2015
Externally publishedYes


  • Dose escalation
  • Niemann-Pick disease type B
  • Nonneuronopathic ASMD
  • Olipudase alfa
  • Recombinant human acid sphingomyelinase

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology


Dive into the research topics of 'Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency'. Together they form a unique fingerprint.

Cite this