Evaluation of Spanish Gaucher disease patients after a 6-month imiglucerase shortage
Introduction
Gaucher disease (GD) is the most common lysosomal storage disorder. It is a recessively inherited disease caused by genetic mutations and rearrangements that lead to deficiencies in the function of the lysosomal enzyme, glucocerebrosidase (EC 3.2.1.45)(OMIM #230800) [1]. This deficiency produces an intracellular accumulation of glucocerebroside, primarily within the reticuloendothelial system. With a prevalence of 1:57,000, GD is clinically characterized by extensive phenotypic heterogeneity, with manifestations ranging from death in utero to asymptomatic individuals. GD can be classified into three clinical subtypes (type 1, 2, and 3), defined by the presence and rate of progression of neurologic manifestations. In the last 20 years, enzyme replacement therapy (ERT) was developed, initially using placentas and alglucerase and later using recombinant technology in CHO cells. Imiglucerase, an ERT manufactured by Genzyme Corporation (MA, USA) is clinically effective for type 1 GD [2], [3], [4]. The recombinant glucocerebrosidase administered intravenously—usually at biweekly intervals for life has improved the quality of life of patients, prevented spleen removal, and improved bone complications. Patients treated with ERT have improved haematological parameters and visceral size, bone disease, and quality of life [2], [3], [4]. Currently, imiglucerase is the only registered enzyme in the European Union (EU). Velaglucerase (VPRIV®, Shire Human genetic Therapies, MA, USA) has recently been approved in the USA, but not yet in the EU. Another enzyme, taliglucerase (UPLYSO®, Protalix Biotherapeutics, Carmiel, Israel), obtained from vegetal cells, is at the final stages of development. The only oral substrate reduction therapy registered for adults with mild or moderate GD is miglustat (Zavesca™ Actelion Therapeutics ) [5].
Recently, an acute shortage of imiglucerase has occurred as a result of viral contamination (vesivirus 2117) and other deficiencies in the production facility. Since June 2009, the EMEA informed physicians in several successive communications about a temporary shortage of imiglucerase [www.ema.europa.eu/humandocs]. In September 2009, a position statement based on the findings of the European Working Group for Gaucher Disease (EWGGD) and European Gaucher Alliance (EGA), established a set of key recommendations about identifying and monitoring at-risk patients threatened [6] and access to alternative treatments for compassionate use, including those that have completed phase 3 clinical trials but have not yet been licensed.
In Spain, the follow-up of patients and the strict compliance of EWGGD recommendation have allowed a profile of the situation to be obtained in a group of adult type 1 GD patients with restricted ERT. There is a short published experience regarding the temporary interruption or permanent reduction of ERT in GD1 patients [7], [8], [9], [10], [11], [12]. We describe what occurred during this exceptional shortage situation with the objective to increase knowledge of treatment effects.
Section snippets
Patients and data collection
In spite of global shortage began in mid June, in Spain the real restrictions starting in September 2009, since this date a total of 50 GD1 patients were analysed before and after the 6-month imiglucerase shortage. Children (< 18 years old) were excluded from analysis, because the dose reduction in Spain has been minimal, as well as patients who switched to another compassionate ERT or miglustat therapy.
Data were obtained from physicians and from the database of the Spanish Gaucher Disease
Results
The general characteristics of the group are described in Table 1. During the shortage, 23 patients (46%) discontinued therapy, referred to as the discontinuation group (DG); 17 patients (34%) had a 50% dose reduction of imiglucerase, referred to as the reduction group (RG), the decision concerning to reduce or discontinue was based in the mean previous dose received and stability of disease according EWGGD rules. The main characteristics of DG and RG patients during follow-up are detailed in
Discussion
The group of GD1 patients analysed during this withdrawal is fairly large, and the genotype distribution is similar to that observed in the Spanish GD Registry [14]; therefore, the patients should be representative of Spanish GD 1 patients receiving ERTs. The scarce number of events observed (8.7%) and the lack of significant changes in blood counts, as well as in spleen and liver size, are probably due to the short period of discontinuation in our series (DG). In contrast, chitotriosidase
Disclosure
All the authors are members of the Spanish Study Group on Gaucher Disease, a group supported by the Spanish Gaucher Disease Foundation (FEETEG). The corresponding author and some of the others authors are researchers at the Aragonés Institute of Public Health (I + CS) and members of the Centro de Investigación Biomédica En Red de Enfermedades Raras (CIBERER), ISCIII, Zaragoza, Spain.
Conflict of interest
The authors have not conflict of interest with the pharmaceutical industry. PG and MP have received consultancy fees from Actelion Pharmaceuticals Ltd. and Shire HGT, and Protalix for participation in clinical trial programs and other projects, and speaker fees for participation in scientific congresses and sponsored events. PG and MP donate all fees to the National Gaucher Foundation, which supports research in the field of lysosomal storage disorders.
The manuscript has not been published and
Acknowledgments
This study was partially supported by the following grants: FIS EC07/90737, FIS PS09/2556, and CIBERER U-752. We thank all members of the SGGD who provided clinical data and samples; the complete list of physicians of the SGGD who contributed is available at: www.feeteg.org. We are also extremely grateful to the patients whose participation made this work possible.
References (19)
- et al.
Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis
Lancet
(2000) - et al.
Force majeure: therapeutic measures in response to restricted supply of imiglucerase (Cerezyme) for patients with Gaucher disease
Blood Cells Mol. Dis.
(2010) - et al.
Cessation of enzyme replacement therapy in Gaucher disease
Genet. Med.
(2002) - et al.
Clinical consequences of interrupting enzyme replacement therapy in children with type 1 Gaucher disease
J. Pediatr.
(2007) - et al.
Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention
Blood
(2004) - et al.
International Collaborative Gaucher Group U.S. Regional Coordinators. Individualization of long-term enzyme replacement therapy for Gaucher disease
Genet. Med.
(2005) - et al.
Gaucher disease
- et al.
Replacement therapy for inherited enzyme deficiency. Use of purified glucocerebrosidase in Gaucher's disease
N Engl J. Med.
(1974) - et al.
Enzyme therapy in type 1 Gaucher disease: comparative efficacy of mannose-terminated glucocerebrosidase from natural and recombinant sources
Ann. Intern. Med.
(1995)
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