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)

Genet Med. 2016 Jan;18(1):34-40. doi: 10.1038/gim.2015.24. Epub 2015 Apr 2.

Abstract

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.Genet Med 18 1, 34-40.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • C-Reactive Protein / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Replacement Therapy / adverse effects
  • Enzyme Replacement Therapy / methods
  • Female
  • Humans
  • Hyperbilirubinemia
  • Interleukin-8 / metabolism
  • Male
  • Middle Aged
  • Niemann-Pick Disease, Type A / drug therapy*
  • Niemann-Pick Disease, Type A / enzymology
  • Niemann-Pick Disease, Type B / drug therapy*
  • Niemann-Pick Disease, Type B / enzymology
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects*
  • Sphingomyelin Phosphodiesterase / administration & dosage
  • Sphingomyelin Phosphodiesterase / adverse effects*
  • Sphingomyelin Phosphodiesterase / deficiency

Substances

  • CXCL8 protein, human
  • Interleukin-8
  • Recombinant Proteins
  • C-Reactive Protein
  • Sphingomyelin Phosphodiesterase
  • olipudase alfa