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Velaglucerase Alfa (VPRIV) Enzyme Replacement Therapy in Patients with Gaucher Disease: Long-Term Data from Phase III Clinical Trials

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Velaglucerase Alfa (VPRIV) Enzyme Replacement Therapy in Patients with Gaucher Disease: Long-Term Data from Phase III Clinical Trials Wright State University CORE Scholar Biomedical, Industrial & Human Factors Biomedical, Industrial & Human Factors Engineering Faculty Publications Engineering 7-2015 Velaglucerase Alfa (VPRIV) Enzyme Replacement Therapy in Patients with Gaucher Disease: Long-Term Data from Phase III Clinical Trials Derralynn A. Hughes Derlis Gonzalez Elena A. Lukina Atul Mehta Madhulika Kabra See next page for additional authors Follow this and additional works at: https://corescholar.libraries.wright.edu/bie Part of the Biomedical Engineering and Bioengineering Commons, and the Industrial Engineering Commons Repository Citation Hughes, D. A., Gonzalez, D., Lukina, E. A., Mehta, A., Kabra, M., Elstein, D., Kisinovsky, I., Giraldo, P., Bavdekar, A., Hangartner, T. N., Wang, N., Crombez, E., & Zimran, A. (2015). Velaglucerase Alfa (VPRIV) Enzyme Replacement Therapy in Patients with Gaucher Disease: Long-Term Data from Phase III Clinical Trials. American Journal of Hematology, 90 (7), 584-591. https://corescholar.libraries.wright.edu/bie/111 This Article is brought to you for free and open access by the Biomedical, Industrial & Human Factors Engineering at CORE Scholar. It has been accepted for inclusion in Biomedical, Industrial & Human Factors Engineering Faculty Publications by an authorized administrator of CORE Scholar. For more information, please contact library- [email protected]. Authors Derralynn A. Hughes, Derlis Gonzalez, Elena A. Lukina, Atul Mehta, Madhulika Kabra, Deborah Elstein, Isaac Kisinovsky, Pilar Giraldo, Ashish Bavdekar, Thomas N. Hangartner, Nan Wang, Eric Crombez, and Ari Zimran This article is available at CORE Scholar: https://corescholar.libraries.wright.edu/bie/111 RESEARCH ARTICLE AJH Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients with Gaucher disease: Long-term data from phase III clinical trials Derralynn A. Hughes,1,2* Derlis E. Gonzalez,3 Elena A. Lukina,4 Atul Mehta,1,2 Madhulika Kabra,5 Deborah Elstein,6 Isaac Kisinovsky,7 Pilar Giraldo,8,9 Ashish Bavdekar,10 Thomas N. Hangartner,11 Nan Wang,12 Eric Crombez,13 and Ari Zimran6 Type 1 Gaucher disease is an inherited lysosomal enzyme deficiency with variable age of symptom onset. Common presenting signs include thrombocytopenia, anemia, hepatosplenomegaly, bone abnormalities, and, additionally in children, growth failure. Fifty-seven patients aged 3–62 years at the baseline of two phase III trials for velaglucerase alfa treatment were enrolled in the single extension study. In the extension, they received every-other-week velaglucerase alfa intravenous infusions for 1.2–4.8 years at 60 U/kg, although 10 patients experienced dose reduction. No patient experienced a drug-related serious adverse event or withdrew due to an adverse event. One patient died following a convulsion that was reported as unrelated to the study drug. Only one patient tested positive for anti-velaglucerase alfa antibodies. Combining the experience of the initial phase III trials and the extension study, significant improvements were observed in the first 24 months from baseline in hematology variables, organ volumes, plasma biomarkers, and, in adults, the lumbar spine bone mineral density Z-score. Improvements were maintained over longer-term treatment. Velaglucerase alfa had a good long-term safety and tolerability profile, and patients continued to respond clinically, which is consistent with the results of the extension study to the phase I/II trial of velaglucerase alfa. EudraCT number 2008-001965-27; www.clinicaltrials.gov identifier NCT00635427. Am. J. Hematol. 90:584–591, 2015. VC 2015 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc. ᭿ Introduction Gaucher disease (GD) is a rare genetic disease caused by mutations in GBA, which encodes a hydrolytic, lysosomal enzyme (glucosylceramidase). When this enzyme is deficient, the major natural glucocerebroside substrates of the enzyme accumulate in cells, notably macrophages, which are most responsible for the visceral pathophysiology in type 1 GD. Type 1 GD can present at variable ages with thrombocytopenia, anemia, hepatosple- nomegaly, bone marrow infiltration, and various focal and generalized bone abnormalities, and additionally in children, with growth failure [1,2]. Current GD-specific treatment, enzyme replacement therapy (ERT) and substrate reduction therapy, is beneficial but not curative, and so patients usually have regular continual dosing. Valuable research into disease outcomes, with and without treatment, has been conducted through Additional Supporting Information may be found in the online version of this article. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 1Department of Haematology, Royal Free Hospital, London, United Kingdom; 2Department of Haematology, University College London, London, United Kingdom; 3Instituto Privado de Hematologıa e Investigacion Clınica – IPHIC, Asuncion, Paraguay; 4Department of Orphan Diseases, Hematology Research Center, Moscow, Rus- sia; 5Pediatrics Department, All India Institute of Medical Sciences, New Delhi, India; 6Gaucher Clinic, Shaare Zedek Medical Center, affiliated with the Hebrew University-Hadassah Medical School, Jerusalem, Israel; 7Hematology Department, Your Health SA, Buenos Aires, Argentina; 8Medicina Metabolica Hereditaria, Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain; 9Grupo de Estudio de Enfermedades Hematologıcas y Metabolicas, Hospital Universitario Miguel Servet, Zaragoza, Spain; 10Pediatric Gastroenterology Department, King Edward Memorial Hospital Research Centre, Pune, India; 11Department of Biomedical, Industrial, & Human Factors Engineering, Wright State University, Dayton, Ohio; 12Biostatistics & Statistical Programming Department, Shire, Lexington, Massachusetts; 13Rare Disease Unit, Shire, Lexington, Massachusetts Conflicts of interest: DAH has received consultancy fees, travel and research grants, and honoraria for speaking from Shire, Genzyme, Protalix Biotherapeu- tics, and Amicus. EAL has received honoraria for traveling and participation in advisory boards from Shire and Genzyme. DEG and MK have no competing interests to declare. AM receives consulting fees from Shire, and his institution has received unrestricted research grants from Shire. DE currently receives travel expenses and honoraria for presentations at professional meetings from Shire. IK has received honoraria from Shire. PG has received consultancy fees from Shire, Genzyme, Protalix Biotherapeutics, and Actelion. AB’s institution received a research grant from Shire for a study in patients with type 3 Gaucher disease. TNH is a consultant to Shire. NW is an employee of Shire. EC is a former employee of Shire. AZ receives consultancy fees from Protalix Biotherapeu- tics; has options in Protalix Biotherapeutics and is a member of its Scientific Advisory Board; receives honoraria from Shire, Genzyme/Sanofi, and Pfizer; and his institution receives support from Genzyme for participation in the International Collaborative Gaucher Group Gaucher Registry and from Shire for partici- pation in the Gaucher Outcome Survey. *Correspondence to: Derralynn A. Hughes, Department of Haematology, Royal Free London NHS Foundation Trust, University College London, Rowland Hill Street, London NW3 2PF, UK. E-mail: [email protected] Contract grant sponsor: Shire. Received for publication: 12 December 2014; Revised: 20 February 2015; Accepted: 12 March 2015 Am. J. Hematol. 90:584–591, 2015. Published online: 19 March 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/ajh.24012 VC 2015 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc. 584 American Journal of Hematology, Vol. 90, No. 7, July 2015 doi:10.1002/ajh.24012 RESEARCH ARTICLE Velaglucerase alfa long-term treatment for GD1: Phase III data GD registries [3–5]. There is, however, also a need for clinical trial result was also positive, the investigator was to contact the Shire medical monitor evidence for long-term drug efficacy and safety, and this should to determine the appropriate course of action. Efficacy assessments. Blood samples were taken approximately every 3 months include data in pediatric patients. to measure hemoglobin concentration, platelet count, chemokine (CAC motif) Velaglucerase alfa is available as an ERT for type 1 GD. Two ligand 18 (CCL18) level, and chitotriosidase activity, and blood samples were taken randomized, parallel-group phase III trials of velaglucerase alfa were yearly for type I collagen telopeptides N- and C-terminal cross-links (NTx and conducted between 2007 and 2009 in treatment-na€ıve patients, CTx; markers of bone turnover). CCL18 and chitotriosidase were measured accord- including children: study identifiers TKT032 (a parallel assessment of ing to the methods described by Boot et al. [11] and Aguilera et al. [12], respec- tively. CTx and NTx were measured using an enzyme-linked immunosorbent assay. two doses) and HGT-GCB-039 (a noninferiority study comparing Patients underwent quantitative abdominal magnetic resonance imaging at velaglucerase alfa with imiglucerase). No patient discontinued from yearly intervals to assess their spleen and liver volumes. Organ volumes were meas- these studies because of an adverse event (AE), and improvements
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