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One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency.
Genet Med. 2021 08; 23(8):1543-1550.GM

Abstract

PURPOSE

To assess olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children.

METHODS

This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52.

RESULTS

Twenty patients were enrolled: four adolescents (12-17 years), nine children (6-11 years), and seven infants/early child (1-5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001).

CONCLUSION

In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints.

Links

PMC Free PDF

Authors+Show Affiliations

Diaz GA
Icahn School of Medicine at Mount Sinai, New York, NY, USA. george.diaz@mssm.edu.
Jones SA
St Mary's Hospital, Manchester University Foundation Trust, University of Manchester, Manchester, UK.
Scarpa M
Regional Coordinating Center for Rare Diseases, University Hospital Udine, Udine, Italy.
Mengel KE
Clinical Science for LSD, SpinCS, Hochheim, Germany.
Giugliani R
Dept Genetics, UFRGS, Medical Genetics Clinical Research Group, HCPA, and INAGEMP, Porto Alegre, Brazil.
Guffon N
Reference Center for Inherited Metabolic Disorders, Femme Mère Enfant Hospital, Lyon, France.
Batsu I
Sanofi, Bridgewater, NJ, USA.
Fraser PA
Sanofi Genzyme, Inc, Cambridge, MA, USA.
Li J
Sanofi, Bridgewater, NJ, USA.
Zhang Q
Sanofi, Bridgewater, NJ, USA.
Ortemann-Renon C
Sanofi, Bridgewater, NJ, USA.

MeSH

AdolescentChildChild, PreschoolEnzyme Replacement TherapyHumansInfantLiverNiemann-Pick Disease, Type ARecombinant ProteinsSphingomyelin Phosphodiesterase

Pub Type(s)

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

Language

eng

PubMed ID

33875845

Clinical Trial Links

Clinical trial which this article describes

Citation

Diaz, George A., et al. "One-year Results of a Clinical Trial of Olipudase Alfa Enzyme Replacement Therapy in Pediatric Patients With Acid Sphingomyelinase Deficiency." Genetics in Medicine : Official Journal of the American College of Medical Genetics, vol. 23, no. 8, 2021, pp. 1543-1550.
Diaz GA, Jones SA, Scarpa M, et al. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genet Med. 2021;23(8):1543-1550.
Diaz, G. A., Jones, S. A., Scarpa, M., Mengel, K. E., Giugliani, R., Guffon, N., Batsu, I., Fraser, P. A., Li, J., Zhang, Q., & Ortemann-Renon, C. (2021). One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genetics in Medicine : Official Journal of the American College of Medical Genetics, 23(8), 1543-1550. https://doi.org/10.1038/s41436-021-01156-3
Diaz GA, et al. One-year Results of a Clinical Trial of Olipudase Alfa Enzyme Replacement Therapy in Pediatric Patients With Acid Sphingomyelinase Deficiency. Genet Med. 2021;23(8):1543-1550. PubMed PMID: 33875845.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. AU - Diaz,George A, AU - Jones,Simon A, AU - Scarpa,Maurizio, AU - Mengel,Karl Eugen, AU - Giugliani,Roberto, AU - Guffon,Nathalie, AU - Batsu,Isabela, AU - Fraser,Patricia A, AU - Li,Jing, AU - Zhang,Qi, AU - Ortemann-Renon,Catherine, Y1 - 2021/04/19/ PY - 2021/01/19/received PY - 2021/03/10/accepted PY - 2021/03/09/revised PY - 2021/4/21/pubmed PY - 2021/9/14/medline PY - 2021/4/20/entrez SP - 1543 EP - 1550 JF - Genetics in medicine : official journal of the American College of Medical Genetics JO - Genet Med VL - 23 IS - 8 N2 - PURPOSE: To assess olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children. METHODS: This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52. RESULTS: Twenty patients were enrolled: four adolescents (12-17 years), nine children (6-11 years), and seven infants/early child (1-5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001). CONCLUSION: In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints. SN - 1530-0366 UR - https://www.unboundmedicine.com/medline/citation/33875845/One_year_results_of_a_clinical_trial_of_olipudase_alfa_enzyme_replacement_therapy_in_pediatric_patients_with_acid_sphingomyelinase_deficiency_ DB - PRIME DP - Unbound Medicine ER -
Grapherence [↓27 ↑32]

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