title: 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).
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Present address: Stony Brook University School of Medicine, Stony Brook, New York, USA.
authors.forename: Margaret M
authors.initials: MM
authors.lastname: McGovern
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Wasserstein
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kirmse
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: W Lane
authors.initials: WL
authors.lastname: Duvall
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schiano
authors.affiliation: Genzyme, a Sanofi Company, Cambridge, Massachusetts, USA.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.affiliation: Genzyme, a Sanofi Company, Cambridge, Massachusetts, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Richards
authors.affiliation: Genzyme, a Sanofi Company, Cambridge, Massachusetts, USA.|Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Cox
mesh_terms: D000328:Adult; D002097:C-Reactive Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy / Q000009:adverse effects / Q000379:methods; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D052536:Niemann-Pick Disease, Type A / Q000188:drug therapy* / Q000201:enzymology; D052537:Niemann-Pick Disease, Type B / Q000188:drug therapy* / Q000201:enzymology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects*; D013108:Sphingomyelin Phosphodiesterase / Q000008:administration & dosage / Q000009:adverse effects* / Q000172:deficiency
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D011994:Recombinant Proteins; D002097:C-Reactive Protein; D013108:Sphingomyelin Phosphodiesterase; C000608782:olipudase alfa
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