title: Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency.
abstract: 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.
authors.affiliation: Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Melissa P
authors.initials: MP
authors.lastname: Wasserstein
authors.affiliation: Manchester Centre for Genomic Medicine, St. Mary's Hospital, CMFT, University of Manchester, Manchester, UK.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Cardiovascular Trials Unit, Central Manchester University Hospital, Manchester, UK.
authors.forename: Handrean
authors.initials: H
authors.lastname: Soran
authors.affiliation: Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Diaz
authors.affiliation: Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Lippa
authors.affiliation: Pathology, Genzyme, a Sanofi company, Cambridge, MA, USA.
authors.forename: Beth L
authors.initials: BL
authors.lastname: Thurberg
authors.affiliation: Clinical and Experimental Pharmacology, Sanofi, Bridgewater, NJ, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Culm-Merdek
authors.affiliation: Clinical and Experimental Pharmacology, Sanofi, Bridgewater, NJ, USA.
authors.forename: Elias
authors.initials: E
authors.lastname: Shamiyeh
authors.affiliation: Global Safety, Genzyme, a Sanofi company, Cambridge, MA, USA.
authors.forename: Haig
authors.initials: H
authors.lastname: Inguilizian
authors.affiliation: Clinical Development, Genzyme, a Sanofi company, Cambridge, MA, USA.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Cox
authors.affiliation: Clinical Development, Genzyme, a Sanofi company, Cambridge, MA, USA. Electronic address: ana-cristina.puga@genzyme.com.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Puga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy; D005260:Female; D006801:Humans; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D052536:Niemann-Pick Disease, Type A / Q000188:drug therapy*; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D013108:Sphingomyelin Phosphodiesterase / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013109:Sphingomyelins / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D015415:Biomarkers; D008055:Lipids; D011994:Recombinant Proteins; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase; C000608782:olipudase alfa
keywords: Dose escalation; Niemann–Pick disease type B; Nonneuronopathic ASMD; Olipudase alfa; Recombinant human acid sphingomyelinase