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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.GM

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

McGovern MM
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.
Wasserstein MP
Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Kirmse B
Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Duvall WL
Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Schiano T
Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Thurberg BL
Genzyme, a Sanofi Company, Cambridge, Massachusetts, USA.
Richards S
Genzyme, a Sanofi Company, Cambridge, Massachusetts, USA.
Cox GF
Genzyme, a Sanofi Company, Cambridge, Massachusetts, USA. Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

MeSH

AdultC-Reactive ProteinDose-Response Relationship, DrugEnzyme Replacement TherapyFemaleHumansHyperbilirubinemiaInterleukin-8MaleMiddle AgedNiemann-Pick Disease, Type ANiemann-Pick Disease, Type BRecombinant ProteinsSphingomyelin Phosphodiesterase

Pub Type(s)

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

Language

eng

PubMed ID

25834946

Citation

McGovern, Margaret M., et al. "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)." Genetics in Medicine : Official Journal of the American College of Medical Genetics, vol. 18, no. 1, 2016, pp. 34-40.
McGovern MM, Wasserstein MP, Kirmse B, et al. 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;18(1):34-40.
McGovern, M. M., Wasserstein, M. P., Kirmse, B., Duvall, W. L., Schiano, T., Thurberg, B. L., Richards, S., & Cox, G. F. (2016). 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). Genetics in Medicine : Official Journal of the American College of Medical Genetics, 18(1), 34-40. https://doi.org/10.1038/gim.2015.24
McGovern MM, et al. 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;18(1):34-40. PubMed PMID: 25834946.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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). AU - McGovern,Margaret M, AU - Wasserstein,Melissa P, AU - Kirmse,Brian, AU - Duvall,W Lane, AU - Schiano,Thomas, AU - Thurberg,Beth L, AU - Richards,Susan, AU - Cox,Gerald F, Y1 - 2015/04/02/ PY - 2014/11/25/received PY - 2015/01/21/accepted PY - 2015/4/4/entrez PY - 2015/4/4/pubmed PY - 2016/11/4/medline SP - 34 EP - 40 JF - Genetics in medicine : official journal of the American College of Medical Genetics JO - Genet Med VL - 18 IS - 1 N2 - 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. SN - 1530-0366 UR - https://www.unboundmedicine.com/medline/citation/25834946/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__ DB - PRIME DP - Unbound Medicine ER -