Novel first-dose adverse drug reactions during a phase I trial of olipudase alfa (recombinant human acid sphingomyelinase) in adults with Niemann-Pick disease type B (acid sphingomyelinase deficiency)

Margaret M. McGovern, Melissa P. Wasserstein, Brian Kirmse, W. Lane Duvall, Thomas Schiano, Beth L. Thurberg, Susan Richards, Gerald F. Cox

Research output: Contribution to journalArticle

19 Scopus citations


Purpose:Enzyme replacement therapy with olipudase alfa (recombinant human acid sphingomyelinase) is being developed for Niemann-Pick disease type B (NPD B).Methods:A single-center, open-label, nonrandomized, single-ascending-dose trial evaluated the safety of intravenous olipudase alfa (0.03-1.0 mg/kg) in 11 adults with NPD B. Patients were monitored in the hospital for 72 h after infusion and had follow-up visits on days 14 and 28.Results:Plasma ceramide, a product of sphingomyelin catabolism by olipudase alfa, showed dose-dependent elevations by 6 h postdose, or postinfusion. No serious adverse drug reactions (ADRs) occurred during the study. Acute phase reaction-type ADRs, as evidenced by elevated inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin-8, and calcitonin) and constitutional symptoms (fever, pain, nausea, and/or vomiting) emerged 12-24 h following doses ≥0.3 mg/kg olipudase alfa. Three patients experienced hyperbilirubinemia. The study was terminated after a patient dosed at 1 mg/kg exhibited severe hyperbilirubinemia; he was subsequently diagnosed with Gilbert syndrome.Conclusion:The maximum tolerated dose of olipudase alfa in adults with NPD B was 0.6 mg/kg. First-dose ADRs were likely induced by elevated concentrations of ceramide (or its downstream derivatives) generated by the catabolism of accumulated sphingomyelin. Within-patient dose escalation to slowly catabolize sphingomyelin stores may be a strategy to mitigate first-dose ADRs in patients with NPD B.

Original languageEnglish (US)
Pages (from-to)34-40
Number of pages7
JournalGenetics in Medicine
Issue number1
StatePublished - Jan 1 2016
Externally publishedYes



  • acute phase reaction
  • ceramide
  • hyperbilirubinemia
  • Niemann-Pick disease type B
  • recombinant human acid sphingomyelinase

ASJC Scopus subject areas

  • Genetics(clinical)

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