دورية أكاديمية
Long-term efficacy and safety of vestronidase alfa enzyme replacement therapy in pediatric subjects < 5 years with mucopolysaccharidosis VII.
| العنوان: | Long-term efficacy and safety of vestronidase alfa enzyme replacement therapy in pediatric subjects < 5 years with mucopolysaccharidosis VII. |
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| المؤلفون: | Lau HA; NYU Grossman School of Medicine, Department of Neurology, New York, NY, USA. Electronic address: Heather.Lau@nyulangone.org., Viskochil D; University of Utah, Department of Pediatrics, Salt Lake City, UT, USA. Electronic address: Dave.Viskochil@hsc.utah.edu., Tanpaiboon P; Rare Disease Institute, Children's National Health System, Washington, DC, USA. Electronic address: PTanpaib@childrensnational.org., Lopez AG; Hospital Universitario Virgen del Rocío and Universidad de Sevilla, Seville, Spain. Electronic address: antonio.gonzalezmeneses.l.sspa@juntadeandalucia.es., Martins E; Centro Hospitalar Universitário do Porto, Hospital de Santo António, Porto, Portugal. Electronic address: esmeralda.dia@chporto.min-saude.pt., Taylor J; Ultragenyx Pharmaceutical Inc., Novato, CA, USA. Electronic address: JTaylor@ultragenyx.com., Malkus B; Ultragenyx Pharmaceutical Inc., Novato, CA, USA. Electronic address: BMalkus@ultragenyx.com., Zhang L; Ultragenyx Pharmaceutical Inc., Novato, CA, USA. Electronic address: LZhang@ultragenyx.com., Jurecka A; Ultragenyx Pharmaceutical Inc., Novato, CA, USA. Electronic address: ajurecka@gmail.com., Marsden D; Ultragenyx Pharmaceutical Inc., Novato, CA, USA. Electronic address: DMarsden@ultragenyx.com. |
| المصدر: | Molecular genetics and metabolism [Mol Genet Metab] 2022 May; Vol. 136 (1), pp. 28-37. Date of Electronic Publication: 2022 Mar 09. |
| نوع المنشور: | Clinical Trial, Phase II; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 9805456 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1096-7206 (Electronic) Linking ISSN: 10967192 NLM ISO Abbreviation: Mol Genet Metab Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Orlando, FL : Academic Press, c1998- |
| مواضيع طبية MeSH: | Mucopolysaccharidosis VII*/therapy, Child ; Enzyme Replacement Therapy ; Glucuronidase ; Glycosaminoglycans/urine ; Hepatomegaly ; Humans ; Hydrolases ; Splenomegaly |
| مستخلص: | Mucopolysaccharidosis (MPS) VII is an ultra-rare, autosomal-recessive, metabolic disease caused by a deficiency of β-glucuronidase, a lysosomal enzyme that hydrolyzes glycosaminoglycans (GAGs), including dermatan sulfate (DS), chondroitin sulfate, and heparan sulfate (HS). β-glucuronidase deficiency leads to progressive accumulation of undegraded GAGs in lysosomes of affected tissues, which may cause hydrops fetalis, short stature, hepatosplenomegaly, and cognitive impairment. An open-label, multicenter, phase II study was conducted in 8 pediatric subjects <5 years of age with MPS VII. Subjects received the recombinant human β-glucuronidase vestronidase alfa 4 mg/kg by intravenous infusion every other week for 48 weeks (treatment period). Those who completed the 48-week treatment were offered to continue treatment with vestronidase alfa 4 mg/kg for up to 240 weeks or until withdrawal of consent, discontinuation, or study termination (continuation period). The level of GAG excreted in urine (uGAG) above normal has been shown to correlate with disease severity and clinical outcomes in MPS diseases. Therefore, the primary efficacy endpoint of this study was to determine the mean percentage change in uGAG DS excretion from baseline to week 48. Statistically significant reductions in uGAG DS from baseline were observed at each visit (p < 0.0001), with a least square mean (standard error) percentage change of -60% (6.6) at week 4 (first post-baseline assessment) and -61% (6.41) at week 48 (final assessment during treatment period). Secondary efficacy endpoints included change from baseline to week 48 in growth and hepatosplenomegaly. Positive trends were observed toward increased standing height Z-score (mean [standard deviation] at baseline, -2.630 [1.17], n = 8; at week 48, -2.045 [0.27], n = 7) and growth velocity (mean [SD] Z-score at baseline, -2.59 [1.49], n = 4; at week 48, -0.39 [2.10], n = 4; p = 0.27). Hepatomegaly was resolved in 3 of 3 subjects assessed by ultrasound and in 5 of 6 subjects assessed by physical examination; splenomegaly was resolved in 1 of 3 subjects assessed by ultrasound and in 2 of 2 subjects assessed by physical examination. There were no new safety signals identified during this study. Mild-to-moderate infusion-associated reactions occurred in 4 (50%) subjects. In conclusion, long-term vestronidase alfa treatment demonstrated a rapid and sustained reduction in uGAGs, maintained growth, and improved hepatosplenomegaly in pediatric subjects with MPS VII <5 years of age. Trial registration: NCT02418455. Competing Interests: Declaration of Competing Interest Heather A. Lau, David Viskochil, Pranoot Tanpaiboon, Antonio Gonzalez-Meneses Lopez, and Esmeralda Martins served as principal investigators for this study. Heather A. Lau is now a full-time employee of Ultragenyx Pharmaceutical Inc.; served on advisory boards for Adult Polyglucosan Body Disease Research Foundation, Amicus Therapeutics, BioMarin Pharmaceutical Inc., Chiesi, Enzyvant, National Tay-Sachs & Allied Diseases Association, Sanofi Genzyme, Takeda, and Taysha Therapeutics; received honoraria from Actelion, Amicus Therapeutics, BioMarin Pharmaceutical Inc., Chiesi, Enzyvant, Fabry Support & Information Group, Muscular Dystrophy Association, National Gaucher Foundation, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical Inc.; served as a consultant for Actelion, Amicus Therapeutics, ASPA Therapeutics, BioMarin Pharmaceutical Inc., Chiesi, Pfizer, Prevail Therapeutics, Sanofi Genzyme, Takeda, Taysha Therapeutics, and Ultragenyx Pharmaceutical Inc.; received grants from National Tay-Sachs & Allied Diseases Association and Sanofi Genzyme; and received research support from Amicus Therapeutics, ASPA Therapeutics, BioMarin Pharmaceutical Inc., Intrabio, Mallinckrodt Pharmaceuticals, Orphazyme, Ovid Therapeutics, Pfizer, Protalix BioTherapeutics, Sangamo Therapeutics, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical Inc. David Viskochil received research support from Levo Therapeutics, Soleno Therapeutics, SpringWorks Therapeutics, Takeda, and Ultragenyx Pharmaceutical Inc.; served on advisory boards for Sanofi Genzyme and Takeda; and received honoraria from AstraZeneca and Sanofi Genzyme. Pranoot Tanpaiboon is an employee of Quest Diagnostics. Antonio Gonzalez-Meneses Lopez has served on advisory boards for Sanofi and Ultragenyx Pharmaceutical Inc., and received payments for travel expenses from Sanofi, Shire, and Ultragenyx Pharmaceutical Inc. Esmeralda Martins received research support from Ultragenyx Pharmaceutical Inc. Julie Taylor, Betsy Malkus, Lin Zhang, and Deborah Marsden are employees and shareholders of Ultragenyx Pharmaceutical Inc. Agnieszka Jurecka is an employee of BridgeBio (formerly an employee of Ultragenyx Pharmaceutical Inc.). (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Growth; Hepatosplenomegaly; Mucopolysaccharidosis VII; Pediatric patients.; Urinary glycosaminoglycan; Vestronidase alfa |
| سلسلة جزيئية: | ClinicalTrials.gov NCT02418455 |
| المشرفين على المادة: | 0 (Glycosaminoglycans) 7XZ4062R17 (vestronidase alfa) EC 3.- (Hydrolases) EC 3.2.1.31 (Glucuronidase) |
| تواريخ الأحداث: | Date Created: 20220325 Date Completed: 20220517 Latest Revision: 20220602 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1016/j.ymgme.2022.03.002 |
| PMID: | 35331634 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1096-7206 |
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| DOI: | 10.1016/j.ymgme.2022.03.002 |