A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase

doi:10.1016/j.bcmd.2014.05.004

Blood Cells, Molecules, and Diseases

Volume 53, Issue 4, December 2014, Pages 253-260

https://doi.org/10.1016/j.bcmd.2014.05.004 Get rights and content

Abstract

Taliglucerase alfa is a β-glucosidase enzyme replacement therapy (ERT) approved in the US and other countries for the treatment of Gaucher disease (GD) in adults and is approved in pediatric and adult patients in Australia and Canada. It is the first approved plant cell-expressed recombinant human protein. A Phase 3, multicenter, open-label, 9-month study assessed safety and efficacy of switching to taliglucerase alfa in adult and pediatric patients with GD treated with imiglucerase for at least the previous 2 years. Patients with stable disease were offered taliglucerase alfa treatment using the same dose (9–60 U/kg body weight) and regimen of administration (every 2 weeks) as imiglucerase. This report summarizes results from 26 adult and 5 pediatric patients who participated in the trial. Disease parameters (spleen and liver volumes, hemoglobin concentration, platelet count, and biomarker levels) remained stable through 9 months of treatment in adults and children following the switch from imiglucerase. All treatment-related adverse events were mild or moderate in severity and transient in nature. Exploratory parameters of linear growth and development showed positive outcomes in pediatric patients. These findings provide evidence of the efficacy and safety profile of taliglucerase alfa as an ERT for GD in patients previously treated with imiglucerase. This trial was registered at www.clinicaltrials.gov as # NCT00712348.

Introduction

Gaucher disease (GD), an autosomal, recessively inherited deficiency of acid β-glucosidase (glucocerebrosidase [EC 3.2.1.45]) [1], [2], is one of the most common of the lysosomal storage disorders [3], and the first to be treated successfully with enzyme replacement therapy (ERT) [4]. GD is clinically heterogeneous and can manifest at any age [1], [5].

Taliglucerase alfa (Elelyso™, Pfizer, New York, NY, USA; Protalix BioTherapeutics, Carmiel, Israel), the first plant cell-expressed recombinant human protein [6], is an approved ERT for adult patients with Type 1 GD in the United States [7], Israel, Australia, Canada, and other countries. Taliglucerase alfa is also approved in pediatric patients in Australia and Canada. Other commercially available human recombinant enzymes for GD include imiglucerase (Cerezyme®, Genzyme Corporation, Cambridge, MA, USA) and velaglucerase alfa (VPRIV®, Shire Human Genetic Therapies, Inc., Lexington, MA, USA). Results of a pivotal, Phase 3, 9-month, double-blind, randomized, parallel-group, multicenter, dose-ranging trial that assessed the safety and efficacy of taliglucerase alfa at 30 U/kg and 60 U/kg in treatment-naïve patients with GD have been reported by Zimran et al. [4]. After 9 months of treatment, statistically significant improvements from baseline with 30 U/kg and 60 U/kg were observed in spleen and liver volumes and hemoglobin concentrations. Improvement in platelet counts at 9 months was statistically significant for taliglucerase alfa 60 U/kg, but not 30 U/kg; all patients achieved an important reduction in chitotriosidase activity by month 9 of treatment.

This report describes the safety and efficacy over the first 9 months of switching to treatment with taliglucerase alfa in adult and pediatric patients with GD previously treated with imiglucerase (study PB-06-002).

Section snippets

Study design

This Phase 3, multicenter, open-label, switchover trial (US National Institutes of Health www.clinicaltrials.gov identifier NCT00712348) [8] was designed to assess the safety and efficacy of the switch to treatment with taliglucerase alfa in adults and pediatric patients (≥ 2 years of age) with GD, who had been receiving imiglucerase ERT for at least 2 years on a stable maintenance regimen (i.e., dose unchanged for at least the 6 months prior to enrollment). The study was conducted at 11 medical

Study patients

The CONSORT flow diagram of study patients is summarized in Fig. 1. A total of 46 patients from 11 study sites across 9 countries were screened; 33 patients were eligible for enrollment. A total of 31 patients received treatment with taliglucerase alfa: median dose ≤ 15 U/kg, n = 8; median dose > 15 to ≤ 30 U/kg, n = 12; and median dose > 30 U/kg, n = 11. Demographics for the 26 adult and 5 pediatric patients who received treatment with taliglucerase alfa are summarized in Table 1; baseline disease

Discussion

In this study, all 30 patients, 25 adults and 5 children, remained clinically stable through 9 months of treatment in all dose groups ranging from a median of 9 to 60 U/kg in adults and from a median of 26 to 60 U/kg in pediatric patients. Patients with GD were previously treated with imiglucerase and switched to taliglucerase alfa at the same dose. Parameters of disease stability, including organ volumes, hemoglobin concentration, platelet count, and biomarker activity, remained stable. Because

Conclusions

At the end of the 9 months of treatment with taliglucerase alfa in this study, all 30 patients, 25 adults and 5 children remained clinically stable (with regard to key GD parameters) at all dose groups ranging from a median of 9 to 60 U/kg in adults and ranging from a median of 26 to 60 U/kg in pediatric patients. These observations reinforce the safety and efficacy profile of taliglucerase alfa in the treatment of adults and children with GD, previously treated with imiglucerase. No unexpected

Author contribution

None of the authors received compensation for their contributions to this manuscript. Drs. Pastores, Petakov, Giraldo, Rosenbaum, Szer, Deegan, Amato, Mengel, Tan, Chertkoff, Brill-Almon, and Zimran conducted research, contributed to the writing of the manuscript, and approved the final manuscript.

Acknowledgments

This study was sponsored by Protalix BioTherapeutics. Editorial and medical writing support was provided by Callie Grimes, PhD, of Peloton Advantage, LLC, and was funded by Pfizer. Pfizer and Protalix entered into an agreement in November 2009 to develop and commercialize taliglucerase alfa.

References (11)

G.M. Pastores et al.
Therapeutic goals in the treatment of Gaucher disease
Semin. Hematol.
(2004)
A. Zimran
How I treat Gaucher disease
Blood
(2011)
A. Zimran et al.
Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease
Blood
(2011)
D. Elstein et al.
Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement
Blood
(2007)
A. Zimran et al.
Lipid storage diseases

There are more references available in the full text version of this article.

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A Phase 3, multicenter, open-label, switchover trial to assess the safety and efficacy of taliglucerase alfa, a plant cell-expressed recombinant human glucocerebrosidase, in adult and pediatric patients with Gaucher disease previously treated with imiglucerase

Abstract

Introduction

Section snippets

Study design

Study patients

Discussion

Conclusions

Author contribution

Acknowledgments

Semin. Hematol.

Blood

Blood

Blood

Lipid storage diseases